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Background: Allgrove syndrome (OMIM 231550) is a rare autosomal recessive disease characterized by non-CAH primary adrenal insufficiency (non-CAH PAI), alacrima, and achalasia. It is caused by mutations in the AAAS gene. The syndrome is also associated with variable progressive neurological impairment and dermatological abnormalities., Methods and Results: We diagnosed 23 patients from 14 families with Allgrove syndrome, based on the presence of at least two characteristic symptoms, usually adrenal insufficiency and alacrima, between 2008 and 2018. A previously described nonsense variant of AAAS was detected in 19 patients from 12 families at homozygous state. Another novel homozygous mutation (c.394-397delCTGT) in AAAS was detected in four patients from two families. Presenting symptoms were alacrima (23/23; 100%), adrenal insufficiency (18/23; 78%), achalasia (13/23; 57%), short stature/growth retardation (16/23; 70%), hyperreflexia (15/23; 65%), palmoplantar hyperkeratosis (13/23; 57%), hyperpigmentation of the skin (10/23; 43%), hypoglycemia-induced convulsion (7/23; 30%), swallowing difficulty and vomiting (6/23; 26%). Serum DHEAS concentrations were low in all patients (23/23; 100%)., Conclusions: Clinical symptoms vary even among patients carrying the same mutation. Triple A syndrome should be considered in the etiology of non-CAH PAI in Arab populations and in Southeast Turkey. Any child with non-CAH PAI should be evaluated for the presence of alacrima and/or achalasia or family history of alacrima and/or achalasia. Children with alacrima and/or achalasia should also be investigated for adrenal insufficiency. Definitive molecular diagnosis is essential for early diagnosis and management of adrenal insufficiency, neurological symptoms, and growth retardation in patients and early diagnosis of as yet asymptomatic cases in the family, together with genetic counseling.

A 38-year-old male patient was admitted with slowly progressive spastic gait disturbance. Imaging revealed general spinal cord atrophy. Because of adrenal insufficiency, alacrima and achalasia, triple A syndrome was suspected. This is a case report of a triple A syndrome patient with a predominance of neurological features and a new heterozygous compound mutation in triple A syndrome gene.

Triple A syndrome is a rare genetic disorder caused by mutations in the achalasia-addisonianism-alacrima syndrome (AAAS) gene which encodes a tryptophan aspartic acid (WD) repeat-containing protein named alacrima-achalasia-adrenal insufficiency neurologic disorder (ALADIN). Northern blot analysis shows that the 2.1 kb AAAS mRNA is expressed in various tissues with stronger expression in testis and pancreas. We show that human ALADIN is a protein with an apparent molecular weight of 60 kDa, and expressed in the adrenal gland, pituitary gland and pancreas. Furthermore, biochemical analysis using anti-ALADIN antibody supports the previous finding of the localization of ALADIN in the nuclear membrane. The mutations S544G and S544X show that alteration of S544 residue affects correct targeting of ALADIN to the nuclear membrane.

Purpose: Triple A syndrome is a rare autosomal recessive disease characterized by achalasia, alacrima, adrenocorticotrophic hormone resistant adrenal failure and some neurologic abnormalities. We report a nine year old patient with alacrima, optic atrophy and achalasia with mutation in the AAAS gene., Methods: PCR amplification of the complete coding sequence as well as the exon-intron junctions of AAAS gene was performed in DNA from the patient and his parents., Results: AAAS gene analysis demonstrated a homozygous A to G mutation at nucleotide position 122 in exon 1 in DNA from the patient., Conclusions: The novel mutation described confirms the diagnosis.

The triple A syndrome is a rare autosomal recessive disease that is characterised by the triad of adrenocorticotropin (ACTH)-resistant adrenal insufficiency, achalasia and alacrima. In most patients, neurological and dermatological abnormalities are associated features. We report on the first Bosnian patient with triple A syndrome. Endocrine investigation confirmed primary adrenal insufficiency at the age of 5.8 years. Two months later, achalasia was diagnosed, and in the presence of alacrima, the patient satisfies the diagnostic criteria of triple A syndrome. In addition, a large number of associated neurological and dermatological features were present in this patient. Moreover, he has dysmorphic facial features, which have not been previously described in triple A syndrome. Triple A syndrome was confirmed by molecular analysis, revealing a nonsense mutation p.W84X in the AAAS gene. The parents are both heterozygous carriers of the mutation. The affected twin brother unfortunately died from hypoglycaemic shock, despite a normal cortisol rise in an ACTH stimulation test. Further, triple A syndrome patients carrying the identical homozygous p.W84X mutation have to be studied to assess a genotype-phenotype relationship for this mutation.

Allgrove syndrome consists of triad of Adrenal hypoplasia, Achalasia cardia and Alacrimia. Often the first manifestation of adrenal hypoplasia is Addisonian crisis precipitated by infection or trauma. We present case of a 9-year-old boy who presented in shock due to adrenal failure later confirmed to have Allgove syndrome.

Objective: Allgrove syndrome is a rare autosomal recessive disorder characterized by the triad of adrenal insufficiency, achalasia and alacrima and many cases have multi-systems disorder: endocrine, gastrointestinal tract, eyes and nervous system. This syndrome is also known as achalasia-addisonianism-alacrima syndrome or triple A syndrome. Allgrove syndrome is now known to be caused by mutations of AAAS gene encoding the aladin protein. In the present paper, we report a Chinese mainland girl with Allgrove syndrome with mutations in the AAAS gene., Method: The patient was a 7-year-old girl complained of coma and dark skin; she was treated as Addison disease for 2 years and had vomiting for 9 months before the second admission. Gene analysis was performed after extracting genomic DNA by amplification and sequencing of the specific fragments of AAA gene., Results: The patient was confirmed to have adrenal insufficiency at the age of 5 years and 6 months. During the second hospitalization, she was found to have a remarkable brisk reflexion, bilateral optic nerve atrophy, alacrima and achalasia besides ACTH resistance. The girl was born to consanguineous parents. Based on these findings, she was diagnosed as having Allgrove syndrome. Mutation analysis revealed a novel homozygous deletion of a single G, c.771delG, in exon 8 of the AAAS gene. This frame shift mutation was predicted to create a premature stop codon at locus 290, p.R258GfsX33, leading to a truncated and non-functioning aladin protein. Both the parents were heterozygous for the mutation., Conclusion: The clinical manifestations and AAAS gene mutations analysis confirmed the diagnosis of Allgrove syndrome. Gene analysis indicated that this syndrome is an autosomal recessive inherent disorder. ALADIN is significant for the normal cell function. When compared with reported cases, it seems that there are no remarkable relation between gene mutation loci and clinical manifestations in Allgrove syndrome.

The triple A or Allgrove's syndrome is an autosomal recessive disorder characterized by the triad of achalasia cardia, alacrima and ACTH resistant adrenocortical insufficiency. Mutations of the Achalasia-Addisonianism-Alacrima-Syndrome (AAAS) gene on chromosome 12q13 are associated with this syndrome. We report an Indian family where two siblings were homozygous for a known mutation of the AAAS gene and presented with the classical triad of symptoms. The mother and the brother were heterozygous and asymptomatic. The affected siblings had iron deficiency anemia and the younger sister had pes cavus and palmoplantar keratosis. Neurological symptoms were absent in both affected children. Recognition of this syndrome can lead to early treatment of adrenal insufficency and genetic counselling.

Triple A syndrome is a human autosomal recessive disorder characterized by adrenal insufficiency, achalasia, alacrima, and neurological abnormalities affecting the central, peripheral, and autonomic nervous systems. In humans, this disease is caused by mutations in the AAAS gene, which encodes ALADIN, a protein that belongs to the family of WD-repeat proteins and localizes to nuclear pore complexes. To analyze the function of the gene in the context of the whole organism and in an attempt to obtain an animal model for human triple A syndrome, we generated mice lacking a functional Aaas gene. The Aaas-/- animals were found to be externally indistinguishable from their wild-type littermates, although their body weight was on the average lower than that of wild-type mice. Histological analysis of various tissues failed to reveal any differences between Aaas-/- and wild-type mice. Aaas-/- mice exhibit unexpectedly mild abnormal behavior and only minor neurological deficits. Our data show that the lack of ALADIN in mice does not lead to a triple A syndrome-like disease. Thus, in mice either the function of ALADIN differs from that in humans, its loss can be readily compensated for, or additional factors, such as environmental conditions or genetic modifiers, contribute to the disease.

Allgrove syndrome (triple A syndrome) is a rare autosomal recessive disorder characterized by achalasia, alacrima, adrenal insufficiency, and--occasionally--autonomic instability. Disease causing mutations have been found in the AAAS gene on 12q13, but no strong phenotype-genotype correlation could be found. We present a 28 year-old woman with classical systemic features of triple A syndrome with prominent neurological dysfunctions/deficits, including distal muscular atrophy, progressive muscle weakness and wasting of both legs, sensibility dysfunction, hyperreflexia and autonomic dysfunction presented with excessive sweating. DNA sequencing of the AAAS gene revealed compound heterozygosity for previously reported mutations. A similar genotype was previously reported, but with a remarkably different phenotype.

Objective: The clinical and molecular data of a patient with triple A syndrome are reported., Patient: A 21-year-old male who was diagnosed for adrenal insufficiency at the age of 2 years after a severe attack of adrenal crisis. At the age of 4 years, achalasia and alacrima were diagnosed. Puberty started at the age of 17 years. At the same time, symptoms of central, peripheral, and autonomic nervous system dysfunction were noted. Later on, at the age of 20 years, a bone age delay of 6 years and severe osteoporosis was diagnosed., Results: A compound heterozygous AAAS mutation consisting of two mutations was found: a C > T transition in exon 7 resulting in a change of arginine at amino acid position 194 into a stop codon (Arg194X) at one allele, and a C > T transition in exon 12 resulting in a change of glutamine at amino acid position 387 into a stop codon (Gln387X) on the other allele., Conclusion: The mutation in exon 7 (p.R194X) of the AAAS gene is a novel mutation which has not been found in any other family so far, whereas the second was already found in some other families. This case adds to the clinical and molecular spectrum of triple A syndrome and may provide a new insight into the functions of AAAS gene., (Copyright (c) 2006 S. Karger AG, Basel.)

Triple A syndrome (AAAS, OMIM#231550) is an autosomal recessive condition characterized by adrenal insufficiency, achalasia, alacrima, neurodegeneration and autonomic dysfunction. Mutations in the AAAS gene on chromosome 12q13 have been reported in several subjects with AAAS. Over the last 5 years, we have evaluated six subjects with the clinical diagnosis of AAAS. Three subjects had mutations in the AAAS gene-- including one novel mutation (IVS8+1 G>A)-- and a broad spectrum of clinical presentations. However, three subjects with classic AAAS did not have mutations in the AAAS gene on both alleles. This finding supports the notion of genetic heterogeneity for this disorder, although other genetic mechanisms cannot be excluded.

Triple A syndrome (Allgrove syndrome) is an autosomal recessive disorder consisting of achalasia, alacrima and Addison insufficiency. We report an 11-year-old girl with predominant symptom of achalasia who was diagnosed as Triple A syndrome almost 3 years after initial presentation.

Unlabelled: We report the cases of two sibs of North African origin with AAAS gene mutation characterized by the heterogeneity of their phenotype. While an 8-y-old boy presented with acute adrenal insufficiency and mental retardation, the diagnosis was suggested by the clinical history of his 6-y-old sister who had symptomatic achalasia and chronic adrenal failure., Conclusion: Our observations corroborate the phenotypic heterogeneity reported in triple A syndrome, and underline the possibility of a variable intra-familial expression.

Achalasia cardia is a very rare entity in children and may go undiagnosed for many months if not suspected. We report a case of a 4 months old child who presented with regurgitation of milk and solids and failure to thrive. She was initially treated as gastro-oesophageal reflux. There was a family history of achalasia cardia in the kins with resultant death in one and grossly delayed milestones in the other. Along with achalasia cardia, our patient had alacrima, which brought attention to the associations of achalasia with 'double A', 'triple A' and the '4 A' syndromes.

We report on the case of a 25-year-old woman with triple A syndrome and gene mutation, who, during the long follow-up period of 23 years, developed myoclonus of the face and the upper limbs (with normal brain magnetic resonance spectroscopy) and widespread digestive dysmotility, involving small bowels and gall bladder. These features, not previously described, illustrate an extension of the cerebral and digestive neurological involvement in this syndrome., (Copyright 2003 Movement Disorder Society)

Objective: To investigate the phenotype and genotype of 3 unrelated children with triple A syndrome from southern Turkey., Methods: The coding sequence of the AAAS gene was sequenced including exon-intron boundaries. Haplotype analysis using markers from AAAS region was performed in order to assess potential founder effects., Results: In all 3 patients, the identical nonsense mutation (R478X) in exon 16 of the AAAS gene was identified. The patients who may be distantly related appeared phenotypically similar with the classical triad of the triple A syndrome (adrenal insufficiency, alacrima and achalasia) with dermatological manifestations while lacking neurological features except for mild mental retardation., Conclusion: The R478X mutation tends to result in a rather severe phenotype although genotype-phenotype relationships cannot be drawn due to the small number of patients., (Copyright 2004 S. Karger AG, Basel)

Primary adrenal insufficiency is an uncommon disease which has worldwide distribution. The commonest cause in underdeveloped countries is tuberculosis followed by autoimmune destruction of the adrenal gland. We report a case of a 15 years boy who had congenital adrenal insufficiency associated with achalasia of the cardia and deficient tear secretion.

We report two siblings with Allgrove's syndrome and extrapyramidal features. Though various neurological abnormalities have been described in this disorder, we report the first patient of Allgrove's syndrome associated with dystonia and chorea.

Triple A syndrome is a human autosomal recessive disorder characterized by an unusual array of tissue-specific defects. Triple A syndrome arises from mutations in a WD-repeat protein of unknown function called ALADIN (also termed Adracalin or AAAS). We showed previously that ALADIN localizes to nuclear pore complexes (NPCs), large multiprotein assemblies that are the sole sites of nucleocytoplasmic transport. Here, we present evidence indicating that NPC targeting is essential for the function of ALADIN. Characterization of mutant ALADIN proteins from triple A patients revealed a striking effect of these mutations on NPC targeting. A variety of disease-associated missense, nonsense, and frameshift mutations failed to localize to NPCs and were found predominantly in the cytoplasm. Microscopic analysis of cells from a triple A patient revealed no morphological abnormalities of the nuclei, nuclear envelopes, or NPCs. Importantly, these findings indicate that defects in NPC function, rather than structure, give rise to triple A syndrome. We propose that ALADIN plays a cell type-specific role in regulating nucleocytoplasmic transport and that this function is essential for the proper maintenance andor development of certain tissues. Our findings provide a foundation for understanding the molecular basis of triple A syndrome and may lead to unique insights into the role of nucleocytoplasmic transport in adrenal function and neurodevelopment.

Allgrove's syndrome, i.e., achalasia, addisonianism, alacrima (OMIM 231550) is an autosomal recessive disorder recently associated with the AAAS gene coding for the Aladin protein. However, the pathophysiology of achalasia in Allgrove's syndrome remains obscure. Here we investigated the histopathology of the cardia in Allgrove's syndrome. Myectomy specimens from 10 children with Allgrove's syndrome and four normal cardia were studied by routine staining and by immunohistochemistry for the pan-neuronal marker PGP9.5, neuronal NO synthase, interstitial cells of Cajal, and CD3+ lymphocytes. In the normal cardia, myenteric ganglia, intramuscular nerve fibers, and interstitial cells of Cajal were numerous, whereas myenteric fibrosis and lymphocyte infiltrates were absent. In Allgrove's syndrome, fibrosis of the intermuscular plane was prevalent in all patients. Myenteric ganglia were absent, decreased, or apparently normal in 1 of 10, 8 of 10, and 1 of 10, respectively. Neuronal NO synthase was absent in 7 of 10 and decreased in 3 of 10, whereas interstitial cells of Cajal appeared normal in 7 of 10 and decreased in 3 of 10. Lymphocytes infiltrating the myenteric plexus were present in 6 of 10. Pyloromyectomy specimens available for six patients showed normal histopathologic features. In conclusion, the lack of neuronal NO synthase and fibrosis of the intermuscular plane can be linked to the defective cardia relaxation. Other features were less constant and may reflect the variability of disease expression and progression among patients with Allgrove's syndrome.

Allgrove's or "4 A" syndrome is a rare autosomal recessive condition with alacrima, achalasia, autonomic disturbance, and ACTH insensitivity among other features. Recent studies have identified mutations in the AAAS, a candidate gene on chromosome 12q13 in such patients. Manifestations in adult patients are rarely reported. The syndrome usually presents during the first decade of life with dysphagia or severe (occasionally fatal) hypoglycaemic or hypotensive attacks, related to adrenocortical insufficiency. Onset of adrenal insufficiency or other features may be delayed to adulthood. In contrast with paediatric patients, adult patients with Allgrove's syndrome may present with multisystem neurological disease; the childhood history of achalasia or alacrima may be overlooked. The authors describe two families with two affected siblings and a further unrelated patient with typical clinical features of Allgrove's syndrome, who exhibit signs of multisystem neurological disease including hyperreflexia, muscle wasting, dysarthria, ataxia, optic atrophy, and intellectual impairment. None of the cases have developed adrenal insufficiency but all have progressive neurological disability. Autonomic dysfunction was a significant cause of morbidity in two cases. The three index cases represent the longest described follow up of Allgrove's syndrome into adulthood. It is speculated that they represent a subgroup of patients who follow an often undiagnosed chronic neurological course. Recognition of the syndrome presenting in adult life permits treatment of unrecognised autonomic dysfunction, adrenal insufficiency and dysphagia, and appropriate genetic advice.

Allgrove syndrome (triple A syndrome) is an autosomal recessive disorder characterised by adrenocortical insufficiency, achalasia and alacrima. Patients also suffer from diverse neurological disorders. Allgrove syndrome is caused by mutations in the AAAS gene located at chromosome 12q13, which encodes for a tryptophan-aspartic acid (WD) repeat protein (aladin). The exact function of this protein is still not known.

The triple A syndrome (MIM*231550) is a rare autosomal recessive disorder characterized by adrenocorticotropic hormone (ACTH) resistant adrenal failure, achalasia, alacrima and a variety of neurological and dermatological features. Adrenal insufficiency usually presents in the first decade of life, however in some patients it may occur later in life or may even lack completely. Recently, we and others identified a novel gene on chromosome 12q13, designated AAAS (Achalasia-Addisonianism-Alacrima-Syndrome gene) which is mutated in patients with triple A syndrome. We investigated n=84 families including 111 patients with clinically suggested triple A syndrome and identified homozygous or compound heterozygous AAAS mutations in 78 families. Genotype/phenotype analyses revealed a highly variable occurrence, age of onset and severity of all clinical symptoms between patients with the same AAAS mutation. The obvious lack of a genotype/phenotype relationship is suggestive of modifying genes/factors which need to be determined. The AAAS protein function is unknown. With four WD repeats it belongs to the family of WD repeat-containing proteins which may exhibit a high degree of functional diversity. The subcellular localization of the protein and the determination of its putative binding partners will shed light on the role of the AAAS protein for the development and function of the adrenal gland and other neuroendocrine structures.

Triple A syndrome, also known as Allgrove syndrome, is a rare autosomal recessive disorder characterized by adrenal insufficiency, achalasia and alacrima. It has recently been reported that this syndrome is caused by mutations in the AAAS gene. In the present study, we analyzed the AAAS gene in a Japanese patient with triple A syndrome. The patient was a Japanese girl previously reported by Hirose et al. (J Jpn Pediatr Soc 102: 912-915, 1998). The parents of the patient were first cousins. The patient was confirmed to have alacrima and isolated glucocorticoid deficiency at the age of 2 years. She later developed achalasia of the cardia, and was diagnosed as having triple A syndrome. The AAAS gene was amplified by the PCR method, and the PCR products were directly sequenced. The patient was homozygous for a novel nonsense mutation Q237X, changing codon 237 encoding Gln (CAA) to a stop codon (TAA). The parents were heterozygous for the Q237X mutation. The AAAS gene encodes a protein of 546 amino acids, ALADIN. The Q237X mutation is predicted to result in a truncated and presumably non-functioning ALADIN protein, thus causing the clinically manifest syndrome in the patient. To our knowledge, this is the first report on AAAS gene mutations in Japan.

For those searching for human disease-causing genes, information on the position of genes with respect to genetic markers is essential. The physical map composed of ESTs and genetic markers provides the positional information of these markers as well as the starting point of gene identification in the form of genomic clones containing exons. To facilitate the effort of identification of genes in the region spanning D12S1629 and D12S312, we constructed a high-resolution transcript map with PAC/BAC/cosmid clones. The strategy for the construction of such a map involved utilization of STSs for the screening of the large insert bacterial chromosome libraries and a chromosome 12-specific cosmid library by hybridization. The contig was constructed based on the STS contents of the clones. The resulting high-resolution transcript map of the region between P273P14/SP6 and D12S312 spans 4.4 cM from 66.8 to 71.2 cM of the Généthon genetic map and represents approximately 2.4 Mb. It was composed of 81 BAC, 45 PAC, and 91 cosmid clones with a minimal tiling path consisting of 16 BAC and 4 PAC clones. These clones are being used to sequence this part of chromosome 12. We determined the order of 135 STSs including 74 genes and ESTs in the map. Among these, 115 STSs were unambiguously ordered, resulting in one ordered marker per 21 kb. The order of keratin type II locus genes was determined. This map would greatly enhance the positional cloning effort of the responsible genes for those diseases that are linked to this region, including male germ cell tumor as well as palmoplantar keratoderma, Bothnian-type, and triple A syndrome. This transcript map was localized at human chromosome 12q13.

The triple A or Allgrove's syndrome (MIM*231550) is an autosomal recessive disease characterized by the triad of adrenocorticotropic hormone (ACTH) resistant adrenal insufficiency, achalasia and alacrima. Since its first description by Allgrove et al. (1978) more than 70 cases from all over the world have been reported. The syndrome manifests itself during the first decade of life with severe hypoglycaemic episodes which can cause sudden death. The frequent association with neurological disorders presenting as a mixed pattern of upper and lower motor neuropathy, sensory impairment, autonomic neuropathy and mental retardation may result in a severely disabling disease. As an additional feature some patients have hyperkeratosis of their palms and soles. We have performed a systematic genome linkage scan in eight triple A families of which three were consanguineous [including the large highly inbred kindred described by Moore et al. (1991)]. We obtained conclusive evidence for linkage of the triple A syndrome locus to markers on chromosome 12q13 (D12S368, theta max = 0, Zmax = 10.81) with no indication of genetic heterogeneity. Haplotype and multipoint analyses suggest that the gene is located on a chromosomal segment flanked by the markers D12S1629 and D12S312 which are 6 cM apart. This region harbors the type II keratin gene cluster, and potential candidate genes include SCN8A and HOXC genes.

Allgrove syndrome (isolated glucocorticoid deficiency, achalasia and alacrima) was found in eight members of an inbred French Canadian/North American Indian pedigree. The high degree of consanguinity supports an autosomal recessive mode of inheritance for this disorder. Six patients presented with hypoglycaemia and other evidence of cortisol deficiency between 2.5 and 8 years of age; however, two others became cortisol deficient after initial testing showed normal cortisol responses to ACTH, evidence that the glucocorticoid insufficiency of this syndrome may not be congenital, but may develop as late as the third decade. No evidence of mineralocorticoid deficiency has been found during 65 patient-years of follow-up. Alacrima was the earliest and most consistent clinical sign of Allgrove syndrome. Other manifestations of peripheral or autonomic neuropathy were found in four patients. The patients showed similar facial features, and three had significant velo-pharyngeal incompetence. All showed oesophageal dysmotility even in the absence of symptomatic dysphagia. In-vitro studies of lymphocyte ACTH binding showed no differences from normal controls. If such lymphocyte binding, as has been suggested, reflects adrenal ACTH receptor activity, these data would suggest that the glucocorticoid deficiency of Allgrove syndrome is not the result of a defect in that receptor. However, the observation that ACTH does not elicit increased adenylate cyclase activity even in normal lymphocytes casts considerable doubt on the physiological significance of ACTH binding to lymphocytes. It seems likely, therefore, that true ACTH receptors are not expressed on peripheral lymphocytes, and any conclusions regarding a possible receptor defect in Allgrove syndrome must await studies of receptor expression on adrenal cell membranes.

We describe a single case of a 2-year, 8-month-old male child with alacrima, achalasia, and neurologic anomalies and proven clinical and laboratory evidence of normal adrenocortical function. As the child was the product of a first cousin marriage, the possibility of autosomal recessive mode of inheritance was considered. Differentiation between this syndrome and other previously described associated syndromes is illustrated. This article emphasizes the presence of multisystem anomalies as described in the presence of normal suprarenal function.

Isolated glucocorticoid failure associated with achalasia of the cardia is described in two pairs of siblings in separate families. Defective tear production is also present in three of the patients, and one shows other signs of autonomic dysfunction. Two other families with adrenal insufficiency and achalasia are known. This unusual association probably represents a familial disorder of as yet unknown aetiology.