Search

Background/Aims: Neonatal onset Urea cycle disorders (UCDs) can be life threatening with severe hyperammonemia and poor neurological outcomes. Glycerol phenylbutyrate (GPB) is safe and effective in reducing ammonia levels in patients with UCD above 2 months of age. This study assesses safety, ammonia control and pharmacokinetics (PK) of GPB in UCD patients below 2 months of age. Methods: This was an open-label study in UCD patients aged 0 – 2 months, consisting of an initiation/transition period (1 – 4 days) to GPB, followed by a safety extension period (6 months to 2 years). Patients presenting with a hyperammonemic crisis (HAC) did not initiate GPB until blood ammonia levels decreased to below 100 μmol/L while receiving sodium phenylacetate/sodium benzoate and/or hemodialysis. Ammonia levels, PK analytes and safety were evaluated during transition and monthly during the safety extension for 6 months and every 3 months thereafter. Results: All 16 patients with UCD (median age 0.48 months, range 0.1 to 2.0 months) successfully transitioned to GPB within 3 days. Average plasma ammonia level excluding HAC was 94.3 μmol/L at baseline and 50.4 μmol/L at the end of the transition period (p = 0.21). No patient had a HAC during the transition period. During the safety extension, the majority of patients had controlled ammonia levels, with mean plasma ammonia levels lower during GPB treatment than baseline. Mean glutamine levels remained within normal limits throughout the study. PK analyses indicate that UCD patients

Classic homocystinuria is due to deficiency of cystathionine beta-synthase (CBS), a pyridoxine-dependent enzyme that, depending on the molecular variants, may be co-factor responsive. Elevated methionine is often used as the primary analyte to detect CBS deficiency (CBSD) on newborn screening (NBS), but is limited by increased detection of other biochemical disorders with less clear clinical significance such as methionine aminotransferase (MAT) I/III heterozygotes. Our state has implemented a two-tier NBS algorithm for CBSD that successfully reduced the number of MATI/III heterozygotes, yet effectively detected a mild, co-factor responsive form of CBSD. After initial diagnosis, newborns with CBSD often undergo a pyridoxine challenge with high-dose pyridoxine to determine responsiveness. Here we describe our NBS-identified patient with a mild form of pyridoxine responsive CBSD who developed respiratory failure and rhabdomyolysis consistent with pyridoxine toxicity during a pyridoxine challenge. This case highlights the need for weight-based dosing and duration recommendations for pyridoxine challenge in neonates.

The increasing demand for advanced genomic services has finally come to the attention of healthcare systems and stakeholders who are now eager to find creative solutions to increase the pool of genomic literate providers. Training in genetics and dysmorphology has historically been conducted as a self-driven practice in pattern recognition, ideally within a formal or informal apprenticeship supervised by a master diagnostician. In recent times, case-based learning, framed by flipped classroom pedagogy have become the preferred teaching methods for complex medical topics such as genetics and genomics. To illuminate this perspective, our article was written in honor of the teaching style and pedagogy of Dr John M. Graham Jr and his lifelong commitment to medical education and mentoring.

Methionine S-adenosyltransferase deficiency, due to mutations in MAT1A, is the most common cause of persistent isolated hypermethioninemia (PIH). While the recessive form may cause neurological consequences, the dominant form is typically benign. This condition may be found in asymptomatic infants through newborn screening programs. We describe 16 asymptomatic individuals with PIH. Our data reiterates the benign nature of PIH and reports two novel mutations in the gene. There were a disproportionate number of individuals with African descent in this cohort.

BACKGROUND: Glutamate formiminotransferase deficiency (FTCD deficiency) or formiminoglutamic aciduria is the second most common of the known inherited disorders of folate metabolism. Initial case reports suggested that patients may have severe intellectual disability and megaloblastic anemia. However, these cases were obtained from screening cohorts of patients with developmental delay. Subsequently, patients with milder clinical phenotypes have been reported. The full phenotypic spectrum of this disorder remains unknown. METHODS: In many states, FTCD deficiency can be incidentally detected on tandem mass spectrometrybased newborn screening of dried blood spots. In this work, we report the outcomes of infants identified to have FTCD deficiency through newborn screening. RESULTS: During the study period, 18 patients were identified to have FTCD deficiency and were referred and evaluated at one of the two participating metabolic centers. The overall rate of FTCD deficiency detected through the New Jersey screening program over the study time period was 1:58,982. At a mean age of 56 months at last follow-up, 3/18 (16%) had developmental delays requiring individualized education plans; no patients had profound intellectual disability. 4/16 (25%) had mild self-limited anemia; no patients had profound anemia. CONCLUSIONS: These data suggest that the majority of individuals with FTCD deficiency detected by newborn screening are asymptomatic.

Methionine adenosyltransferase I/III deficiency, also known as Mudd's disease, is a rare inborn error of methionine metabolism. Because pathophysiological mechanisms of the disease remain poorly understood, the consequences of this disorder and the need for medical management remain uncertain; likewise, the effect of medical interventions on clinical outcomes in Mudd's disease is largely unknown due to a relative lack of published longitudinal clinical data. There are few reports of adults in the medical literature affected with this disease. Clinical symptoms of reported adults range from asymptomatic to individuals with neurological, developmental, or behavioral symptoms. Here we report three siblings affected with Mudd's disease that were ascertained following an abnormal newborn screen for hypermethioninemia in the case of our index patient. All three had a variable degree of longstanding neurologic or psychiatric symptoms which had not prompted a clinical investigation for a genetic or metabolic disorder prior to identification through our clinic. While the causal association of these symptoms to the metabolic disorder remains unclear in these cases, all three patients demonstrated a degree of amelioration of symptoms and/or improvement in measurements on standardized psychiatric ratings scales when specific therapy for the metabolic disorder was instituted. The symptoms, treatment, and outcomes over the course of six years of follow-up are presented here, expanding the possible natural history of Mudd's disease.

Background Dysphagia following a cervical fusion is a known complication; however, this has not been examined in the trauma population. We sought to identify risk factors that can be optimized in this population. Methods We performed a retrospective chart review on consecutive trauma patients who underwent a cervical fusion from 2014 to 2017 at a single institution with multiple surgeons. We included patients more than 18-years-old who were admitted through the emergency department with a diagnosis of acute cervical injury and underwent a cervical fusion during the same admission. We excluded patients who remained intubated postoperatively or underwent a tracheostomy. The primary outcome was dysphagia as evaluated by a bedside swallow test on postoperative day one by the nursing staff. This was followed by a standardized assessment performed by a speech therapist on postoperative day two in some cases. Variables of interest included sex, age, mechanism of injury, surgical approach, cervical levels, and Charlson comorbidity index. Univariate analysis was also utilized. Results Sixty patients met the study criteria. Nineteen patients (31.7%) developed dysphagia postoperatively. Mechanical falls were the most common injury mechanism (80%) and most surgical procedures were performed on the subaxial cervical spine (68.3%). Comparing the dysphagia groups, there was no significant difference among the confounding variables. Patients with dysphagia had an increased length of stay (10.6 ± 6.7 vs. 7.4 ± 3.1, p = 0.056) and were more likely to have had an anterior vs. posterior cervical fusion (63.2% vs. 34.1%, p = 0.056). Conclusions We found no statistically significant risk factors leading to postoperative dysphagia. The objective of this pilot is to find the baseline dysphagia rate and the potential modifiable factors in this unique patient population undergoing cervical fusion procedures.

Classic galactosemia (CG) is a potentially lethal genetic disorder that results from profound loss of galactose-1-phosphate uridylyltransferase (GALT). CG is detected by newborn screening (NBS) in many countries; however, conclusive diagnosis can be complex due to broad and overlapping ranges of GALT activity. Molecular studies can also be complex due to allelic heterogeneity at the GALT locus.We conducted both biochemical and molecular follow-up studies for an infant flagged by NBS for possible galactosemia. To clarify the diagnosis we also conducted biochemical and RNA studies of lymphoblasts prepared from the child and one parent.We identified a novel noncoding GALT variant, c.377+17CT, that was homozygous in the child and heterozygous in both parents. The child and both parents also showed diminished GALT activity in red blood cells, and transformed lymphoblasts from the child and one parent further showed diminished GALT activity. However, qRT-PCR studies demonstrated apparently normal GALT mRNA levels in lymphoblasts, and Gal-1P values measured in the child following galactose exposure in infancy and at 1 year were normal.These results highlight the existence of rare but apparently benign variants in GALT and underscore the need for functional studies to distinguish pathogenic from benign variants.

Biotinidase deficiency, if untreated, usually results in neurological and cutaneous symptoms. Biotin supplementation markedly improves and likely prevents symptoms in those treated early. All states in the United States and many countries perform newborn screening for biotinidase deficiency. However, there are few studies about the outcomes of the individuals identified by newborn screening.We report the outcomes of 142 children with biotinidase deficiency identified by newborn screening in Michigan over a 25-year period and followed in our clinic; 22 had profound deficiency and 120 had partial deficiency.Individuals with profound biotinidase and partial deficiency identified by newborn screening were started on biotin therapy soon after birth. With good compliance, these children appeared to have normal physical and cognitive development. Although some children exhibited mild clinical problems, these are unlikely attributable to the disorder. Biotin therapy appears to prevent the development of neurological and cutaneous problems in our population.Individuals with biotinidase deficiency ascertained by newborn screening and treated since birth appeared to exhibit normal physical and cognitive development. If an individual does develop symptoms, after compliance and dosage issues are excluded, then other causes must be considered.Genet Med 17 3, 205-209.

Women with inherited metabolic disorders, including those with previously life-limiting conditions such as MMA, are reaching child-bearing age more often due to advances in early diagnosis and improved pediatric care. Information surrounding maternal and fetal complications associated with the underlying disorders remains largely unexplored.Pregnancies affected by maternal MMA were ascertained through study 04-HG-0127 "Clinical and Basic Investigations of Methylmalonic Acidemia and Related Disorders" (clinicaltrials.gov identifier: NCT00078078) and via literature review. Prenatal and delivery records in study participants were reviewed.Seventeen pregnancies were identified in women with isolated MMA, including three abortions, one termination, and 13 completed pregnancies [three cases with cblA (four pregnancies), four cases of mut- (one cobalamin responsive, three non-responsive), five cases with unknown type of MMA]. Seventeen percent (3/17) of the pregnancies resulted in a first trimester abortion, while 38.5% (5/13) of the completed pregnancies resulted in preterm deliveries. A cesarean delivery rate of 53.8% (7/13) was noted among the cohort. Fetal distress or nonreassuring fetal status was the indication for 57% (4/7) cesarean deliveries. One patient was reported to have metabolic crisis as well as episodes of mild hyperammonemia. Malformations or adverse outcomes in the progeny were not observed.Although there have been a small number of pregnancies identified in women with MMA, the cumulative results suggest that the majority of pregnancies can be complicated by cesarean delivery and increased risk of prematurity. A pregnancy registry could clarify perinatal complications and define management approaches needed to ensure optimal maternal and fetal outcomes in this growing patient population.

Biotinidase deficiency (BD) is an autosomal recessive disorder resulting in the inability to recycle the vitamin biotin. Individuals with biotinidase deficiency can develop neurological and cutaneous symptoms if they are not treated with biotin. To date, more than 165 mutations in the biotinidase gene (BTD) have been reported. Essentially all the mutations result in enzymatic activities with less than 10% of mean normal serum enzyme activity (profound biotinidase deficiency) with the exception of the c.1330G>C (p.D444H) mutation, which results in an enzyme having 50% of mean normal serum activity and causes partial biotinidase deficiency (10-30% of mean normal serum biotinidase activity) if there is a mutation for profound biotinidase deficiency on the second allele. We now reported eight novel mutations in ten children identified by newborn screening in Michigan from 1988 to the end of 2012. Interestingly, one intronic mutation, c.310-15delT, results in an approximately two-fold down-regulation of BTD mRNA expression by Quantitative real-time reverse-transcription PCR (qRT-PCR). This is the first report of an intronic mutation in the BTD gene with demonstration of its effect on enzymatic activity by altering mRNA expression. This study identified three other mutations likely to cause partial biotinidase deficiency. These results emphasize the importance of full gene sequencing of BTD on patients with biotinidase deficiency to better understand the genotype and phenotype correlation in the future.

Mosaicism is increasingly recognized as a cause of developmental disorders with the advent of next-generation sequencing (NGS). Mosaic mutations of PIK3CA have been associated with the widest spectrum of phenotypes associated with overgrowth and vascular malformations. We performed targeted NGS using 2 independent deep-coverage methods that utilize molecular inversion probes and amplicon sequencing in a cohort of 241 samples from 181 individuals with brain and/or body overgrowth. We identified PIK3CA mutations in 60 individuals. Several other individuals (n = 12) were identified separately to have mutations in PIK3CA by clinical targeted-panel testing (n = 6), whole-exome sequencing (n = 5), or Sanger sequencing (n = 1). Based on the clinical and molecular features, this cohort segregated into three distinct groups: (a) severe focal overgrowth due to low-level but highly activating (hotspot) mutations, (b) predominantly brain overgrowth and less severe somatic overgrowth due to less-activating mutations, and (c) intermediate phenotypes (capillary malformations with overgrowth) with intermediately activating mutations. Sixteen of 29 PIK3CA mutations were novel. We also identified constitutional PIK3CA mutations in 10 patients. Our molecular data, combined with review of the literature, show that PIK3CA-related overgrowth disorders comprise a discontinuous spectrum of disorders that correlate with the severity and distribution of mutations., The clinical and molecular spectrum of PIK3CA-related developmental disorders are correlated with types of mutations, tissue distributions, and levels of mosaicism with the clinical phenotype.

Wiedemann-Rautenstrauch syndrome, also known as neonatal progeroid syndrome, is a rare condition with fewer than 40 patients reported in the literature. Characteristic physical findings include neonatal progeroid appearance, sparse scalp hair, prominent scalp veins, and lipoatrophy; in addition, neonatal teeth are often a distinctive finding. The inheritance pattern of this disorder has been postulated to be autosomal recessive, although a specific gene has not been identified. Here we report an infant with the characteristic phenotypic features of Wiedemann-Rautenstrauch syndrome in whom exome sequencing identified two pathogenic variants in POLR3A: c.1909+18G>A; p.(Y637Cfs*23) and c.2617C>T; p.(R873*). Mutations in POLR3A (OMIM #614258) are associated with 4H leukodystrophy syndrome characterized by the triad of hypomyelination, hypodontia, and hypogonadotrophic hypogonadism. The present patient's genotype implies a broader phenotypic range for POLR3A mutations and might expand the clinical spectrum. This proband is notable because she had two null pathogenic variants. Replication in other patients clinically diagnosed with Wiedemann-Rautenstrauch syndrome is needed to further demonstrate this gene-disease association. © 2016 Wiley Periodicals, Inc.

The macrocephaly-capillary malformation syndrome (M-CM), which we here propose to rename the megalencephaly-capillary malformation syndrome (MCAP; alternatively the megalencephaly-capillary malformation-polymicrogyria syndrome), and the more recently described megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH) are two megalencephaly (MEG) disorders that involve a unique constellation of physical and neuroimaging anomalies. We compare the features in 42 patients evaluated for physical and neuroimaging characteristics of MCAP and MPPH and propose a more global view of these syndromes based on classes of developmental abnormalities that include primary MEG and growth dysregulation, developmental vascular anomalies (primarily capillary malformations), distal limb anomalies (such as syndactyly and polydactyly), cortical brain malformations (most distinctively polymicrogyria, PMG), and variable connective tissue dysplasia. Based on these classes of developmental abnormalities, we propose that MCAP diagnostic criteria include progressive MEG with either vascular anomalies or syndactyly. In parallel, we propose that MPPH diagnostic criteria include progressive MEG and PMG, absence of the vascular anomalies and syndactyly characteristic of MCAP, and absence of brain heterotopia. © 2012 Wiley Periodicals, Inc.

Purpose Pompe disease (PD) is a progressive metabolic myopathy for which the only available treatment is alglucosidase alfa (Myozyme®). Enzyme replacement therapy (ERT) has improved ventilator-free survival, and cardiac and motor functions in patients with infantile PD. However, for an adequate response to occur, a large amount of enzymes must be infused. In some patients, this may be problematic due to infusion-associated reactions (IARs) occurring in approximately 50% of patients receiving alglucosidase alfa infusions. Whilst the majority of these reactions are mild, life threatening hypersensitivity reactions may occur in some patients. In these patients desensitization is indicated to enable continued ERT safely. Infants and young children with PD and significant infusion reactions pose unique management challenges because of their young age, limited communication skills, variable presentation and underlying cardiomyopathy. Methods/subjects In 2 patients with PD who experienced significant ERT-related reactions: an infant (IgE positive) and a young child (IgE negative), we implemented a desensitization protocol, that started by administering a reduced dose of alglucosidase alfa (10 mg/kg weekly) instead of the standard (20 mg/kg bi-weekly) using serial micro-dilutions that were individually prepared and delivered in a highly regulated manner based on patients' clinical manifestations and tolerance. Results Successful desensitization was achieved in both patients, allowing them to eventually continue to receive the full dose of ERT safely. Conclusion Therapeutic demands in infants and young children with PD need to be tailored according to the patient presentation, and underlying cardiac and fluid-volume status. Desensitization allowed both patients to continue alglucosidase alfa treatment at the recommended dose without prolonged interruption of therapy, or further reactions.

✓The authors report on three patients with a congenital brain overgrowth syndrome, macrocephaly–cutis marmorata telangiectatica congenita (M-CMTC), who experienced neurological sequelae associated with herniation of the cerebellar tonsils through the foramen magnum. In two of these patients, the authors document postnatal brain overgrowth that contributed to recurrent descent of the cerebellar tonsils and complicated the surgical treatment in one of the patients. The authors address the neurosurgical concerns related to this syndrome with special attention to acquired tonsillar ectopia and postulate that some patients may be at risk for progressive tonsillar herniation and consequent neurological symptoms due to cerebellar overgrowth. Ectopic cerebellar tonsils have been reported previously in cases of M-CMTC, and this phenomenon may be a secondary event associated with brain overgrowth rather than due to a congenitally small posterior fossa.

Congenital disorders of glycosylation (CDG) comprise a clinically and biochemically heterogeneous group of monogenetic-inherited, multisystemic diseases that affect the biosynthesis of N- and/or O-glycans linked to glycoconjugates. Recently, we identified the first patient with a defect in the cytosolic-orientated GDP-mannose:Man(3-4) GlcNAc(2)-PP-dolichol alpha-1,2-mannosyltransferase (ALG11), who presented an accumulation of shortened dolichol-linked oligosaccharides leading to CDG-Ip (ALG11-CDG). Here we describe an improved metabolic labeling method that allowed the identification of three new CDG-Ip cases that were missed so far in routine diagnostics. Although all CDG-Ip patients carry different mutations in the ALG11 gene, they share a variety of clinical syndromes like an unremarkable prenatal period followed by developmental delay, psychomotor, and mental retardation, strabismus convergens and seizures occurring in the first year of life.

High sustained antibody titers complicate many disorders treated with a therapeutic protein, including those treated with enzyme replacement therapy, such as Pompe disease. Although enzyme replacement therapy with alglucosidase alfa (Myozyme) in Pompe disease has improved the prognosis of this otherwise lethal disorder, patients who develop high sustained antibody titers to alglucosidase alfa enter a prolonged phase of clinical decline resulting in death despite continued enzyme replacement therapy. Clinically effective immune-tolerance induction strategies have yet to be described in the setting of an entrenched immune response characterized by high sustained antibody titers, wherein antibody-producing plasma cells play an especially prominent role.We treated three patients with infantile Pompe disease experiencing marked clinical decline due to high sustained antibody titers. To target the plasma cell source of high sustained antibody titers, a regimen based on bortezomib (Velcade) was used in combination with rituximab, methotrexate, and intravenous immunoglobulin.The treatment regimen was well tolerated, with no obvious side effects. Patient 1 had a 2,048-fold, and patients 2 and 3 each had a 64-fold, reduction in anti-alglucosidase alfa antibody titer, with concomitant sustained clinical improvement.The addition of bortezomib to immunomodulatory regimens is an effective and safe treatment strategy in infantile Pompe disease, with potentially broader clinical implications.

Megalencephaly-capillary malformation (MCAP) and megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndromes are sporadic overgrowth disorders associated with markedly enlarged brain size and other recognizable features(1-5). We performed exome sequencing in 3 families with MCAP or MPPH, and our initial observations were confirmed in exomes from 7 individuals with MCAP and 174 control individuals, as well as in 40 additional subjects with megalencephaly, using a combination of Sanger sequencing, restriction enzyme assays and targeted deep sequencing. We identified de novo germline or postzygotic mutations in three core components of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway. These include 2 mutations in AKT3, 1 recurrent mutation in PIK3R2 in 11 unrelated families with MPPH and 15 mostly postzygotic mutations in PIK3CA in 23 individuals with MCAP and 1 with MPPH. Our data highlight the central role of PI3K-AKT signaling in vascular, limb and brain development and emphasize the power of massively parallel sequencing in a challenging context of phenotypic and genetic heterogeneity combined with postzygotic mosaicism.

Here, we report the neuroimaging findings and neurological changes in 17 unpublished patients with Macrocephaly-Capillary Malformation (M-CM). This syndrome has been traditionally known as Macrocephaly-Cutis Marmorata Telangiectatica Congenita (M-CMTC), but we explain why M-CM is a more accurate term for this overgrowth syndrome. We analyzed the 17 patients with available brain MRI or CT scans and compared their findings with features identified by a comprehensive review of published cases. White matter irregularities with increased signal on T2-weighted images were commonly observed findings. A distinctive feature in more than half the patients was cerebellar tonsillar herniation associated with rapid brain growth and progressive crowding of the posterior fossa during infancy. In four such cases, we confirmed that the tonsillar herniation was an acquired event. Concurrently, with the development of these findings, ventriculomegaly (frequently obstructive) and dilated dural venous sinuses were observed in conjunction with prominent Virchow-Robin spaces in many of those in whom cerebellar tonsil herniation had developed. We postulate that this constellation of unusual features suggests a dynamic process of mechanical compromise in the posterior fossa, perhaps initiated by a rapidly growing cerebellum, which leads to congestion of the venous drainage with subsequently compromised cerebrospinal fluid reabsorption, all of which increases the posterior fossa pressure and leads to acquired tonsillar herniation. We make a distinction between congenital Chiari I malformation and acquired cerebellar tonsil herniation in this syndrome. We also observed numerous examples of abnormal cortical morphogenesis, including focal cortical dysplasia, polymicrogyria which primarily involved the perisylvian and insular regions, and cerebral and/or cerebellar asymmetric overgrowth. Other findings included a high frequency of cavum septum pellucidum or vergae, thickened corpus callosum, prominent optic nerve sheaths and a single case of venous sinus thrombosis. One patient was found to have a frontal perifalcine mass resembling a meningioma at age 5 years. This is the second apparent occurrence of this specific tumor in M-CM.

We have identified a recurrent de novo pericentromeric deletion in 16p11.2-p12.2 in four individuals with developmental disabilities by microarray-based comparative genomic hybridization analysis. The identification of common clinical features in these four individuals along with the characterization of complex segmental duplications flanking the deletion regions suggests that nonallelic homologous recombination mediated these rearrangements and that deletions in 16p11.2-p12.2 constitute a previously undescribed syndrome.

Autosomal recessive infantile osteopetrosis (ARIO) is a rare and potentially fatal disorder of bone metabolism caused by a defect in osteoclast function. The pathologic features are secondary to insufficient bone resorption and usually present in the infancy. Symptoms include sclerotic bones leading to bone marrow compromise with resultant pancytopenia, cranial nerve impingement, hydrocephalus, and fracture. This is an autosomal recessive disorder caused by mutations in either TCIRG1, CLCN7, or OSTM1. Malformations are not a part of this disorder. We present a 6-month-old male, the first child between nonconsanguineous parents, who was referred to our clinic for limb defects. Findings prompting the referral included congenital left upper limb anomalies of syndactyly and radial-ulnar synostosis. There was an ipsilateral anterior rib defect, though there was no clinically appreciable hypoplasia of the pectoralis major. He also had a left low-lying, cross-fused kidney. Besides the limb anomalies, the patient presented in our clinic having signs of hydrocephalus. He had left facial nerve palsy and oculomotor abnormalities. The diagnosis of ARIO was made after hospitalization; radiographs demonstrated characteristic findings of diffuse osteosclerosis and periosteal thickening in all bones. The patient had surgical management for noncommunicating hydrocephalus with good results. The majority of cases with ARIO are compound heterozygotes. Reported homozygous patients most commonly result from a consanguineous mating or come from an isolated population (Costa Rica). Genetic testing of this patient revealed homozygosity for a rare mutation in TCIRG1, a subunit of the osteoclast vacuolar proton pump. Because this child was a product of a nonconsanguineous union, this was an unexpected result. To explain the malformations in this case, we postulated either uniparental disomy or a spontaneous contiguous gene deletion on one chromosome that included the TCIRG1 gene, which then unmasked a hemizygous recessive state. Subsequent sequence analysis of both parents for TCIRG1 mutations showed that each was a heterozygous carrier of their son9s mutation. The presence of the limb and kidney anomalies complicated the diagnosis in this case. No other reported patients with ARIO have had similar birth defects. Without treatment, early demise secondary to bone marrow failure is predicted in nearly all cases. Associated features, natural history, and management recommendations for ARIO will be reviewed.

Oto-Palato-Digital (OPD) syndrome has recently been determined to be caused by mutations in Filamin A, encoded by the FLNA gene on Xq28. Filamin A is a structural protein which is expressed in diverse tissues and functions in cytoskeleton organization. Mutations in different functional domains of the protein result in similar but distinct disorders, including OPD types 1 and 2, Melnick-Needles syndrome, and frontometaphyseal dysplasia. OPD-1 was first characterized by Taybi in 1962 and over 30 cases have since been described in the literature. Principal features include broad forehead, hypertelorism, cleft palate, short stature, conductive hearing loss, and various anomalies of the hands and feet including broad (spatulate) toes, clinodactyly, syndactyly, and mild to moderate mental retardation. Female heterozygotes typically exhibit a milder phenotype with regard to all salient features, with normal intelligence, subtle facial dysmorphism, and mild involvement of the fingers or toes. OPD-2, first delineated by Fitch in 1976, presents a dramatically more severe phenotype in all respects, with frequent early lethality in affected males and a phenotype in female carriers that closely approximates males with OPD-1. Patients with OPD have been described whose phenotypes fall between the two disorders, suggesting a spectrum of severity rather than distinct clinical entities. We report a 22 year old female with dysmorphic features resembling OPD-2, including short stature, wide forehead, hypertelorism, antimongoloid slant to palpebral fissures, low-set, posteriorly rotated ears, small mandible, submucosal cleft palate with bifid uvula, clinodactyly and camptodactyly, broad distal digits, and flexion contractures. Radiographs reveal Klippel-Feil anomaly and spondylolysis of L5-S1, uncommon but reported findings in this condition. This patient also exhibits marked keloid formation at surgical scars, focal myocardial hypertrophy which necessitated surgical resection, and a bicornuate uterus. Neither the tissue overgrowth, nor the uterine malformation has been described previously in reported cases of females with OPD. A review of the literature will be presented with comparison of the findings in this patient to those in other reported females. Data on mutational analysis in females with this disorder is limited to date. Molecular analysis is planned and will be reported if available.