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Infants with limb reduction deficiencies (LRD) often have other associated congenital anomalies. The purpose of this investigation was to assess the prevalence and the types of associated anomalies in a defined population. The associated anomalies in infants with LRD were collected in all livebirths, stillbirths and terminations of pregnancy during 29 years in 387,067 consecutive births in the area covered by our population-based registry of congenital malformations. Of the 317 infants bom with LRD during this period, representing a prevalence of 8.2 per 10,000, 59.9% had associated anomalies. There were 27 (8.5%) cases with chromosomal abnormalities including 17 trisomies 18, and 73 (23.0%) nonchromosomal recognized dysmorphic conditions including 19 VA(C)TER(L) association and 15 Poland syndrome. However, numerous other recognized dysmorphic conditions were registered. Ninety (28.4%) of the cases had multiple congenital anomalies (MCA). Anomalies in the musculoskeletal, the cardiac, the urogenital, and the central nervous system were the most common other anomalies. This study included special strengths: each affected child was examined by a geneticist, all elective terminations were ascertained, and the surveillance for anomalies was continued until 2 years of age. Therefore the overall prevalence of associated anomalies, which was more than one in two infants, emphasizes the need for a thorough investigation of infants with LRD. A routine screening for other anomalies especially in the musculoskeletal system, the cardiovascular system, the urogenital system, the central nervous system, and the digestive system may be considered in infants and in fetuses with LRD.

Cases with congenital diaphragmatic hernia (CDH) often have other associated anomalies. The purpose of this investigation was to assess the prevalence and the types of associated anomalies in CDH in a defined population. The anomalies associated with CDH were collected in all live births, stillbirths and terminations of pregnancy during 29 years in 386,088 consecutive pregnancies of known outcome in the area covered by our population based registry of congenital anomalies. Of the 139 cases with CDH born during this period (total prevalence of 3.60 per 10,000), 85 (61.2%) had associated major anomalies. There were 25 (18.0%) cases with chromosomal abnormalities including 12 trisomies 18, and 24 (17.3%) nonchromosomal recognized dysmorphic conditions. There were no predominant recognized dysmorphic conditions, but Fryns syndrome. However, other recognized dysmorphic conditions were registered including fetal alcohol syndrome, de Lange syndrome, sequences (laterality sequence and ectopia cordis), and complexes (limb body wall complex). Thirty six (25.9%) of the cases had non syndromic multiple congenital anomalies (MCA). Anomalies of the cardiovascular system (n = 53, 27.5%), the urogenital system (n = 34, 17.6%), the musculoskeletal system (n = 29, 15.0%), and the central nervous system (n = 19, 9.8%) were the most common other congenital anomalies. We observed specific patterns of anomalies associated with CDH which emphasizes the need to evaluate all patients with CDH for possible associated malformations. In conclusion the overall prevalence of associated anomalies, which was close to two in three infants, emphasizes the need for a thorough investigation of cases with CDH. A routine screening for other anomalies may be considered in infants and in fetuses with CDH. One should be aware that the anomalies associated with CDH can be classified into a recognizable anomaly, syndrome or pattern in more than one out of two cases with CDH.

Infants with radial ray deficiencies very often have other associated congenital anomalies. The reported frequency and types of associated malformations vary between different studies. The purpose of this investigation was to assess the frequency and types of associated malformations among infants with radial ray deficiencies in a geographically well-defined population from 1979 to 2004 of 346,831 consecutive births. Of the 73 infants with radial ray deficiencies born during this period (prevalence at birth of 2.1 per 10,000), 75% had associated malformations. Infants with associated malformation were divided into recognizable conditions (16 (22%) infants with chromosomal and 20 (27%) with non chromosomal conditions), and non recognizable conditions (19 (26%) infants with multiple malformations). Trisomies 18 and autosomal deletions were the most frequent chromosomal abnormalities. VACTERL association, thrombocytopenia absent radii syndrome, Fanconi anemia and Holt-Oram syndrome were most often present in recognizable non chromosomal conditions. Malformations in the musculoskeletal, cardiovascular and urogenital systems were the most common other anomalies in infants with multiple malformations and non recognizable conditions. The frequency of associated malformations in infants with radial ray deficiencies emphasizes the need for a thorough investigation of these infants. Routine screening for other malformations especially musculoskeletal, cardiac and urogenital systems anomalies may need to be considered in infants with radial ray deficiencies, and referral of these infants for genetic evaluation and counseling seems warranted.

The etiology of congenital diaphragmatic hernia (CDH) is unclear and its pathogenesis is controversial. Because previous reports have inconsistently noted the type and frequency of malformations associated with CDH, we assessed these associated malformations ascertained between 1979 and 2003 in 334,262 consecutive births. Of the 115 patients with the most common type of CDH, the posterolateral, or Bochdalek-type hernia, 70 (60.8%) had associated malformations. These included: chromosomal abnormalities (n = 21, 30.0%); non-chromosomal syndromes (Fryns syndrome, fetal alcohol syndrome, De Lange syndrome, CHARGE syndrome, Fraser syndrome, Goldenhar syndrome, Smith-Lemli-Opitz syndrome, multiple pterygium syndrome, Noonan syndrome, and spondylocostal dysostosis); malformation sequences (laterality sequence, ectopia cordis); malformation complexes (limb body wall complex) and non syndromic multiple congenital anomalies (MCA) (n = 30, 42.9%). Malformations of the cardiovascular system (n = 42, 27.5%), urogenital system (n = 27, 17.7%), musculoskeletal system (n = 24, 15.7%), and central nervous system (n = 15, 9.8%) were the most common other congenital malformations. We observed specific patterns of malformations associated with CDH which emphasizes the need to evaluate all patients with CDH for possible associated malformations. Geneticists and pediatricians should be aware that the malformations associated with CDH can often be classified into a recognizable malformation syndrome or pattern (57.1%).

Infants with neural tube defects (NTDs) may have other associated congenital defects. The reported incidence and the types of associated malformations vary between different studies. The purpose of this investigation was to assess the prevalence of associated malformations in a geographically defined population. The prevalences at birth of associated malformations in infants with NTDs were collected between 1979 and 2003 on all infants born in the area covered by the registry of congenital anomalies of Northeastern France in 334,262 consecutive births. Of the 360 infants with NTDs born during this period, 20.5 % had associated malformations. Associated malformations were more frequent in infants who had encephalocele (37.5 %) than in infants with anencephaly (11.8 %) or infants with spina bifida (23.7 %). Malformations in the face (oral clefts), in the musculoskeletal system, in the renal system, and in the cardiovascular system were the most common other anomalies. In conclusion the overall prevalence of malformations, which was one in five infants, emphasizes the need for a thorough investigation of infants with NTDs. A routine screening for other malformations especially facial clefts, musculoskeletal, renal and cardiac anomalies may need to be considered in infants with NTDs, and genetic counseling seems warranted in most of these complicated cases.

Familial cylindromatosis: we report a daughter with turban tumor and her mother with cylindromatosis. The dermal eccrine cylindroma arose as small, solitary lesions on the head of the mother when she was 28 years old. The following years other tumors became apparent. She was operated on several times. The first lesions appeared on the frontal part of the scalp of the daughter when she was 23 years old. Other tumors grew on the scalp. Histopathological examination of the excised tumors showed the same lesions in both the mother and the daughter: dermal eccrine cylindromata. Family history showed that the daughter's maternal aunt had a few tumors. Dermal eccrine cylindroma should be differentiated from malignant syndromes such as basal naevoid carcinoma or metastases and from neurofibromata. The gene of familial cylindromatosis was localised to chromosome 16q12-q13 and it was proposed that this gene is a tumor supressor gene.

Brachydactyly type E in two sibs with increased bone density and mental retardation. A new autosomal recessive syndrome?: We report on two sibs, a boy and a girl, with syndromic brachydactyly type E. Parents were first cousins. Facial dysmorphia was characterized by a flat occiput, a large forehead, hypertelorism, a long triangular nose, an everted lower lip, downslanting palpebral fissures and strabismus. They had marked shortening of the third, fourth and fifth fingers and of the third, fourth, and fifth toes. IQ was 16 in the boy, 63 in the girl. In both sibs ophtalmologic examination showed strabismus, absence of cataract and normal fundus and radiological findings disclosed increased bone density involving the skull, the vertebrae and the corticalis of the long bones. Neither ectopic calcifications, nor exostosic, nor osteomalacia, and nor osteotis fibrosa cystica were present. Investigations revealed that plasma calcium, phosphate, vitamine D, parathyroid hormone (PTH), response to exogenous PTH, and Gs activity were normal as well as renal and thyroid function. Molecular genetic studies failed to identify mutations in the GNAS 1 gene, in the PTH receptor gene and in the HOX D13 gene. Analysis of 2q showed that there was no deletion 2q37. Other known syndromes with brachydactyly type E and mental retardation were excluded. In conclusion we suggest that these two sibs with a combination of brachydactyly, mental retardation and increased bone density have a specific autosomal recessive syndrome.

Hypophosphatasia is a rare autosomal recessive inborn error of metabolism characterized by a defective bone mineralisation and deficiency of serum and tissue liver/bone/kidney alkaline phosphatase activity. We report the characterisation of tissue-nonspecific alkaline phosphatase (TNSALP) gene mutation in a patient affected by infantile hypophosphatasia. This boy was the first child of non affected, non related parents. At 1 month of age he presented with palsy of the left upper limb with hypotonia. Length was - 2SD. The anterior fontanel was large. There was a markedly decreased ossification of all bones. All limbs were shortened. Ultrasonographic examination of the kidneys showed nephrocalcinosis. Level of alkaline phosphatases was decreased in the child as well as in the parents. Bone density was decreased. At 2 years of age development was delayed. Weight was - 3,5 SD and OFC - 3SD. The child had craniosynostosis. Molecular studies showed 2 missense mutations, both in exon 6 of the TNSALP gene.

Patterned pigmentary disturbances are seen in a large variety of human genetic disorders. Cytogenetic studies have provided evidence that such skin lesions often reflect chromosomal mosaicism. In addition to the well-known pattern of Blaschko's lines a classification of several distinct types was proposed by Happle. This report add the case of a boy with an unusual mosaic-like distribution of skin pigmentation and a further chromosomal anomaly which has not been described in pigmentary mosaicism previously. The proband was born after an uneventful pregnancy and delivery. Developmental milestones were delayed. A generalised hirsutism was noted with a facial dysmorphia: coarse facies. short philtrum, synophris, and large low set years. Hyperpigmentation followed a checkerboard pattern: alternating squares of pigmentary anomalies with a sharp midline separation. Cytogenetic findings Included a normal karyotype (peripheral blood) and a mosaicism 12q;14q translocation (70% of fibroblasts). The present case stresses the importance of careful chromosomal analysis of different tissues in patients with pigmentary anomalies.

Netherthon syndrome is a rare autosomal recessive disease characterized by ichthyosis, the characteristic hair abnormality trichorrhexis invaginata and atopic manifestations. We report a female child with the severe hypernatremic dehydration form of the Netherton syndrome born as the first child of consanguineous parents. Ichthyosis was present at birth. She was admitted to the intensive care unit at the age of 4 days with important loss of weight and dehydration. Severe hypernatremia and convulsions occurred. Despite intensive care the baby died at the age of 11 days. The diagnosis of Netherton syndrome was confirmed by the finding of the pathognomonic hair shaft anomaly trichorrhexis invaginata (bamboo hair) and premature lamellar body secretion and foci of electron-dense material in the intercellular spaces of stratum corneum as relatively specific markers for Netherton syndrome. Netherton syndrome is characterized by a large variability in phenotypic expression. The major neonatal complication is the hypernatremic dehydration, which can be fatal as in this patient or complicated by neurologic signs (intracranial hemorrhage) and secondary sequellae. Molecular studies revealed a mutation in SPINK 5, encoding a serine protease inhibitor. Prenatal diagnosis was performed in the second pregnancy and showed that the fetus was equally affected.

In 1977 Rautenstrauch and Snigula reported on two sisters with a previously undescribed, progeria-like syndrome. Two years later Wiedemann described two unrelated males with the same condition. Since than only a few published cases appeared in the literature. We had the opportunity to study a boy affected by this extremely rare condition. This boy was born after intrauterine growth retardation. At birth two natal teeth were present. OFC was normal despite apparent macrocephaly. During infancy a progeroid appearance was noted with sparse hair, prominent scalp veins, greatly widened anterior fontanelles, malar hypoplasia, and generalized lipoatrophy. The face was triangular with a small maxilla and a protuding chin, the eyes were low-set, the eyebrows and eyelashes were scanty. At the age of 3.5 years there was striking general deficiency of subcutaneous fatty tissue apart from accumulation of adipose tissue on the buttocks and flanks, growth was retarded, mental development was at the low borderline of normal. Cholesterolemia was at the upper range of normal, there was an increase of triglycerides: 3.31 mmol/L (Normal < 1 mmol/L). Other progeroid syndromes such as Hutchinson-Guilford, Berardinelli-Seip, De Barsy, leprechaunism, Cockayne and Hallerman-Streiff could be excluded as well as the CDG syndrome. This condition is most probably inherited as an autosomal recessive trait.

Dyssegmental dysplasia is a rare micromelic dwarfism with characteristic clinical and radiological features. In skeletal dysplasias with severe micromelia prenatal detection of affected fetuses is possible using ultrasonography. However, prenatal diagnosis is usually performed after the occurrence of a previous case in the family. In this case dyssegmental dysplasia was detected prenatally in the first child of unaffected related (first cousins) parents. Fetal ultrasonographic examination in the 33rd week of gestation revealed a normal biparietal diameter of 94 mm and pronounced shortening of the extremities with femurs of 19 mm. The femurs were bowed. The spine showed severe malsegmentation. At radiological examination the long bones showed a dumbbell configuration especially in the longer extremities. The spine showed severe malsegmentations including coronal and sagittal clefting and multiple outsize vertebrae. The pelvis had very narrow sacrosciatic notches and rounded iliac wings. This case supports the autosomal recessive inheritance and demonstrates the possibility of prenatal diagnosis in non familial cases in this type of micromelic dwarfism.

Congenital bilateral fibular deficiency with facial dysmorphia, brachydactyly and mental retardation in which are combined in a syndrome or which do not fit in any of the known syndromes. We report a child with congenital bilateral deficiency of the fibula and an unusual combination of features. The patient, a girl, was born after an uneventful pregnancy at term to young healthy parents. Absent fibulae were noted at birth. At age 4 she was found to have growth retardation with delayed bone age, overlapping, short toes, syndactyly of the toes, clinodactyly of the 5th and 2nd fingers, syndactyly of the three last fingers and facial dysmorphia. Mental retardation was present. Karyotype and laboratory investigations were normal. Differential diagnosis included syndromes with aplasia or hypoplasia of fibula, but none of these syndromes seemed to include the girl's features.

Congenital absence of third molars is common. However absence of the other permanent teeth is relatively rare. Absence of teeth may be isolated or associated to other features. We had the opportunity to examine a girl with oligodontia associated to microcephaly, to facial dysmorphia and to short stature.

Hereditary lymphedema can appear at birth or later up to adulthood. It may be seen in connection with diverse symptoms forming various syndromes. The authors report a family with hereditary lymphedema, brachydactyly, syndactyly and tachycardia. Lymphedema and tachycardia could appear together by chance. However this combination could also be a syndrome.

Binder syndrome or maxillonasal dysplasia is characterized by maxillary hypoplasia and a flat, vertical nose. Inheritance is uncertain. We report on a mother and her son with Binder syndrome. The proband was the last child of a kinship of seven children. Three sisters, three brothers and the parents were normal. The proband had a maxillary hypoplasia and a flat, vertical nose. The columella was short, the nostrils had a triangular shape and the upper lip was convex with an acute nasolabial angle. There were no dental abnormalities apart from those secondary to malocclusion. Height and intelligence were normal. After an uncomplicated pregnancy, the proband delivered a boy who had low nasal bridge, hypertelorism, maxillary hypoplasia and a small nose with a broad columella. Although the majority of cases of maxillonasal dysplasia are sporadic, familial occurrence has been reported by a number of authors. In six pedigrees the recurrence was in second or third degree relatives. Recurrence in sibs with unaffected parents has been observed seven times and an affected parent and child has been rarely reported. The Binder phenotype may be heterogeneous. The pattern of abnormalities seen in this condition does not represent a causally defined entity.

We report two familial cases of oto-palato-digital (OPD) Type II syndrome, a father and his son. This family shows that OPDII syndrome is inherited as an autosomal dominant condition. The similarities between the OPDII syndrome and the Larsen syndrome are discussed.

A girl with short stature and brachydactyly had a fragile site at 16q22. Her mother had the same phenotype and the fragile site, too. These cases open the discussion of a possible association between a rare fragile site and an abnormal phenotype. Fragile sites are divided into two major groups, those which are rate and those which are common. The fragile site at 16q22 is a rare inductible fragile site. It is possible that the association between brachydactyly and the fragile site in a mother and her daughter may be due to chance. However rare fragile sites predispose to phenotypic abnormalities. The abnormal features in these two cases could be the result of the disruption of a gene involved in a skeletal development.

A 23-year-old pregnant woman was referred to the Genetics Department for genetic counselling and possible prenatal diagnosis because of unexplained mental retardation in a paternal uncle. Family history revealed that her father had two mentally retarded sisters well as a brother with mental retardation and a normal sister. This normal sister had two normal sons, on normal daughter and one mentally retarded daughter. The normal daughter had one daughter, who has been referred to the pediatric department because of mental retardation two months earlier; Rett syndrome was diagnosed as this girl had the classical symptoms of this syndrome. The paternal uncle of the consultant was examined. H head typical features of fragile X syndrome. Therefore cytogenetic and molecular studies were undertaken in this family. Fragile X syndrome was diagnosed in the girl with Rett syndrome by the presence of the classical FMR-1 mutation and confirmed by cytogenetic studies, which revealed 12% fragile X positive cells.

The female proband, from Turkish extraction was the fifth liveborn child of a 24-years-old mother and a 25-years-old father. Her parents as well as her two older sisters and her two older brothers were phenotypically normal. Parents were first cousins. At birth a complex cardiac defect was diagnosed (tricuspid atresia, hypoplasia of the pulmonary artery, dextroposition of the aorta, ventricular septal defect and auricular septal defect) for which she was operated on in 1976, 1983 and 1984. When she was 20 years old, latero aortic pheochromocytoma was diagnosed. At physical examination she had microcephaly (-3DS), mild dysmorphia: long pyramidal nose, short philtrum, short fingers and toes and scoliosis and 6 "café-au-lait" macules suggesting neurofibromatosis, type I. Complex congenital heart defect, microcephaly and pheochromocytoma in a patient with neurofibromatosis type I born from consanguineous parents might be a new association.

We report a patient with a sporadic case of oto-palato-digital (OPD) syndrome type II. Parents and five previous sibs are normal. At 26 years of age the patient had conductive hearing impairment, cleft palate, a prominent forehead, a flat facies, and a broad nasal base resulting in the characteristic "pugilistic" appearance. Extension and supination were limited at the elbows; thumbs and halluces were broad. Many radiological abnormalities were noted: malformations of the cervical spine, pelvic abnormalities, bilateral coxa valga, genu valgum, small fibulae, pes equino varus, and 15 carpal bones. IQ improved dramatically from 65 to 95.

Von Recklinghausen neurofibromatosis (NF1) is one of the most common autosomal dominant disorders and has one of the highest mutation rates of a single human locus. The NF1 gene has recently been mapped to proximal 17q. Poland anomaly consists of the combination of unilateral aplasia of the sternal head of the pectoralis major muscle and an ipsilateral anomaly of the hand. Although other defects may occur in patients with Poland anomaly, neurofibromatosis 1 has not been reported. We have seen a boy with these two disorders.

We report on three sibs (two females, one male) with a syndrome including physical and mental developmental delay, facial dysmorphia, an increased number of skin folds and recurrent infections. Pulmonary infections were especially severe and frequent, leading to bronchiectasis. Steatorrhea was intermittent. A sweat test was normal. Congenital heart defect was present in two sibs and vesico-ureteral reflux was diagnosed in two sibs. Neutropenia was the most obvious immunological defect. Myelodysplasia was noted. Acute myeloblastic leukemia developed in one sib. The healthy parents of the patients are first cousins. The consanguinity of the parents points-to an autosomal recessive mode of inheritance of this new syndrome but a mitochondrial disorder cannot be excluded.

We report two sibs with Angelman syndrome or an apparently new syndrome. In addition to severe mental retardation and seizures, clinical examination showed an ataxic and stiff legged gait, truncal hypotonia with hypertonia of the limbs, dysmorphic facial features (brachycephaly, large mouth, pointed chin and a prominent jaws) and scoliosis. Brain CT scan and MRI revealed ventricular enlargement and squared frontal horns. Pregnancy and delivery were uneventful. Karyotypes were normal. No deletion of chromosome 15q11-13 region was shown by molecular genetic techniques. The parents who are normal are second cousins. The condition is therefore probably inherited as an autosomal recessive one.

Twelve patients with hemihypertrophy are described. All but one are sporadic cases. The parents were unrelated. Family and pregnancy histories are otherwise unremarkable in all cases. Diagnosis was always performed at birth or in the weeks following birth. There were 5 boys and 7 girls including one mother and her daughter. Hemihypertrophy was localized to the upper limb in one case and to the lower limb in one case. One patient had some features of Mc Cune Albright syndrome. Hemihypertrophy was associated with Silver-Russel syndrome in two patients. In all other cases hemihypertrophy was idiopathic. Mental and motor development were normal in all cases, as was puberty. During growth the body asymmetry was unchanged. Orthopedic problems complicated growth in some cases. The most obvious of these problems was scoliosis. Limb lengthening was necessary in 2 cases. One of our patients developed an abdominal tumor. One of our patients had two normal children. Hemihypertrophy is usually not inherited. However, the mother of one of our patients also had hemihypertrophy.

Ectodermal dysplasia with arthrogryposis is an uncommon condition. We describe two daughters of a distant consanguineous couple with oligodentia, enamel abnormalities, camptodactyly, longitudinally broken nails, growth retardation, joint contractures with amyotrophy, hypohidrotic skin with tendency to excessive bruising and scarring after injuries and scratching, kypho-scoliosis, mild facial dysmorphia and microcephaly. The condition is probably due to an autosomal recessive gene, the parents being gypsies of the same ancestral origin.

A boy with MCA/MR and a fragile site (FS) at 8q22 opens the discussion of a possible association between a rare autosomal FS and an abnormal phenotype. The child was born after prenatal diagnosis of ureterohydronephrosis. He had facial dysmorphia and mental retardation (IQ = 40). The karyotype showed 8q22 FS in 12% of the cells obtained after addition of FUdR to the culture medium. No other etiologic factor was shown to be responsible for the MCA/MR syndrome. Several authors have reported a variety of neurodevelopmental abnormalities and mental retardation in individuals with rare FS expressed on chromosomes 2, 9, 10, 16 and 19. If rare FS predispose to phenotypic abnormalities what are the mechanisms?