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Background The association of cutaneous hyperpigmented, hypertrichotic, and indurated patches associated with hearing loss, short stature, cardiac anomalies, hepatosplenomegaly, scrotal masses, and hypogonadism has not, to our knowledge, been previously recognized as a disease entity. Objective We describe 10 patients with the above-mentioned findings. Methods Patients were clinically examined and extensive laboratory evaluation was performed. Results We describe 10 patients from 6 Arab consanguineous families with hyperpigmented, hypertrichotic, and indurated cutaneous patches involving the middle and lower parts of their bodies. In addition, patients displayed short stature, sensorineural hearing loss, cardiac anomalies, hepatosplenomegaly, and scrotal masses. Laboratory evaluation revealed growth hormone deficiency and hypergonadotropic hypogonadism with azoospermia. Cutaneous histopathologic examination showed hyperpigmentation of the basal layer with seborrheic-keratosis-like acanthosis, histiocytic infiltration, and a perivascular mononuclear infiltrate with plasma cells and mast cells throughout the dermis and subcutaneous fat. Comparison with several patients, recently reported in the medical literature, with similar cutaneous findings is made. Limitations Laboratory evaluation in some patients was incomplete because of lack of cooperation. Conclusions We suggest that our patients represent a novel multisystemic autosomal recessive inherited disorder. We call this constellation of symptoms the "H syndrome."

We report on a new family with Teunissen-Cremers syndrome. The proband presented with congenital conductive hearing loss due to stapes ankylosis and incus short process fixation with skeletal anomalies including symphalangism, broad thumbs and broad first toes, syndactyly, brachydactyly, contractures of the elbows and knees, hyperopia and lens opacities. This constellation of symptoms is compatible with the diagnosis of one of the joint-fusion syndromes namely the Teunissen-Cremers syndrome (TCS), which was first reported in 1990. Mutations in the NOG gene which encodes the noggin protein, a bone morphogenetic protein antagonist, have been identified in TCS as well as in four other autosomal dominant disorders including proximal symphalangism (SYM1), multiple synostosis (SYNS1), Tarsal-Carpal coalition syndrome and brachydactyly type B (BDB). Interestingly, we found that the mutation P35S described in this family has already been reported in patients affected with SYM1 as well as with BDB syndromes.

Background Human β-mannosidosis, a rare disorder of oligosaccharide catabolism, results from a deficiency of β-mannosidase activity. So far, mutational analysis has been performed in only seven families and revealed 11 mutations in the MANBA gene which encodes the enzyme β-mannosidase. Objectives We report here a 36-year-old Arab female with β-mannosidosis who presented with mental retardation and multiple angiokeratomas. We describe in this patient a novel null mutation and review the previously reported MANBA gene mutations and their clinical correlations. Methods Histopathology, ultrastructural analysis, and enzyme assays were performed. Sequencing of cDNA and genomic DNA analysis was conducted in a search for a mutation in the MANBA gene. Results Histopathology of a skin biopsy specimen from the patient showed the characteristic findings of angiokeratoma. Electron microscopy showed cytoplasmic vacuolation. Enzymatic activity of β-mannosidase in the patient's serum, leukocytes, and fibroblasts was less than 1% of control values. Sequencing of the MANBA cDNA revealed a G→A transition in exon 6 at nucleotide position c.693, resulting in the formation of a stop codon (W231X). Limitations Only one family was studied. Conclusions A new case of human β-mannosidosis is presented and the first MANBA gene mutation from Arab ancestry is reported. Reviewing the reported MANBA gene mutations does not reveal a clear genotype–phenotype correlation. The importance of angiokeratoma corporis diffusum as the clue to the diagnosis of β-mannosidosis and other lysosomal storage diseases is emphasized.

Deficiency of the hepatic cytosolic enzyme tyrosine aminotransferase (TAT) causes marked hypertyrosinaemia leading to painful palmoplantar hyperkeratoses, pseudodendritic keratitis and variable mental retardation (oculocutaneous tyrosinaemia type II or Richner–Hanhart syndrome). Parents may therefore seek prenatal diagnosis, but this is not possible by biochemical assays as tyrosine does not accumulate in amniotic fluid and TAT is not expressed in chorionic villi or amniocytes. Molecular analysis is therefore the only possible approach for prenatal diagnosis and carrier detection. To this end, we sought TAT gene mutations in 9 tyrosinaemia II patients from three consanguineous Palestinian kindreds. In two kindreds (7 patients), the only potential abnormality identified after sequencing all 12 exons and exon–intron boundaries was homozygosity for a silent, single-nucleotide transversion c.1224G > T (p.T408T) at the last base of exon 11. This was predicted to disrupt the 5′ donor splice site of exon 11 and result in missplicing. However, as TAT is expressed exclusively in liver, patient mRNA could not be obtained for splicing analysis. A minigene approach was therefore used to assess the effect of c.1224G > T on exon 11 splicing. Transfection experiments with wild-type and c.1224G > T mutant minigene constructs demonstrated that c.1224G > T results in complete exon 11 skipping, illustrating the utility of this approach for confirming a putative splicing defect when cDNA is unavailable. Homozygosity for a c.1249C > T (R417X) exon 12 nonsense mutation (previously reported in a French patient) was identified in both patients from the third kindred, enabling successful prenatal diagnosis of an unaffected fetus using chorionic villous tissue.

Mutations in the gene NPHS2 encoding podocin are responsible for a recessive form of steroid-resistant nephrotic syndrome (SRNS). The common phenotype is of massive proteinuria in early childhood that tends to progress to end-stage renal failure. Extrarenal manifestations have not been described. Twenty-two children with SRNS from six unrelated Arab families were found to be homozygous for the R138X mutation in NPHS2. Eighteen patients underwent cardiac evaluation at diagnosis of SRNS while they had normal BP and preserved renal function. Cardiac anomalies were detected in 16 (89%) children: Left ventricular hypertrophy in eight, pulmonary stenosis in six, discrete subaortic stenosis in two, and Ebstein anomaly and ventricular septal defect in one each. The remaining four affected individuals were assessed only once they had end-stage renal failure. They had severe left ventricular hypertrophy and experienced repeated episodes of heart failure. Two control groups were equally evaluated. The first consisted of 37 siblings without nephrotic syndrome, of whom only one carrier had a cardiac defect (P < 0.001). None of the second group, which included 22 children with persistent nephrotic syndrome as a result of other causes, had a cardiac anomaly (P < 0.001). Cardiac disorders in homozygotes for mutations in NPHS2 cannot be attributed to an association by chance or to a state of persistent nephrotic syndrome. Because human podocin mRNA is expressed in fetal heart, it is speculated that it may have a role in normal cardiac development. Cardiac evaluation is recommended at the time of diagnosis of SRNS due to mutations in podocin.

Kabuki syndrome is a multiple congenital anomaly/mental retardation syndrome. This study of Kabuki syndrome had two objectives. The first was to further describe the syndrome features. In order to do so, clinical geneticists were asked to submit cases-providing clinical photographs and completing a phenotype questionnaire for individuals in whom they felt the diagnosis of Kabuki syndrome was secure. All submitted cases were reviewed by four diagnosticians familiar with Kabuki syndrome. The diagnosis was agreed upon in 48 previously unpublished individuals. Our data on these 48 individuals show that Kabuki syndrome variably affects the development and function of many organ systems. The second objective of the study was to explore possible etiological clues found in our data and from review of the literature. We discuss advanced paternal age, cytogenetic abnormalities, and familial cases, and explore syndromes with potentially informative overlapping features. We find support for a genetic etiology, with a probable autosomal dominant mode of inheritance, and speculate that there is involvement of the interferon regulatory factor 6 (IRF6) gene pathway. Very recently, a microduplication of 8p has been described in multiple affected individuals, the proportion of individuals with the duplication is yet to be determined.

The microphthalmia with linear skin defects (MLS) syndrome (MIM 309801) is a severe and rare developmental disorder, which is inherited as an X-linked dominant trait with male lethality. In the vast majority of patients, this syndrome is associated with terminal deletion of the Xp22.3 region. Thirty-five cases have been described to date in the literature since the first description of the syndrome in the early 1990s. We now report on the clinical, cytogenetic, and molecular characterization of 11 patients, 7 of whom have not been described previously. Seven of these patients have chromosomal abnormalities of the short arm of the X-chromosome, which were characterized and defined by fluorescence in situ hybridization (FISH) analysis. Intriguingly, one of the patients displays an interstitial Xp22.3 deletion, which to the best of our knowledge is the first reported for this condition. Finally we report on the identification and molecular characterization of four cases with clinical features of MLS but apparently normal karyotypes, verified by FISH analysis using genomic clones spanning the MLS minimal critical region, and with genome-wide analysis using a 1 Mb resolution BAC microarray. These patients made it possible to undertake mutation screening of candidate genes and may prove critical for the identification of the gene responsible for this challenging and intriguing genetic disease.

The N-acetylglucosaminyl-1-phosphotransferase (termed phosphotransferase) catalyzes the initial step in the formation of mannose 6-phosphate (M6P) residues required for the efficient transport of soluble lysosomal enzymes. The phosphotransferase is a multisubunit enzyme composed of three subunits (alpha2beta2gamma2) that are products of two genes. The gene encoding the gamma-subunit (GNPTAG) appears to be defective in patients with mucolipidosis type III (ML III). We have analyzed the GNPTAG gene in two siblings with ML III showing elevated activities of several lysosomal enzymes in cultured fibroblasts serum and diminished activities in cultured fibroblasts. Immunoprecipitation of metabolically labeled cathepsin D (CtsD) from fibroblasts revealed that the sorting/transport of this lysosomal protease was affected. Addition of ammonium chloride inhibiting pH-dependent processes, such as the CtsD-M6P receptor interaction, indicated that 15 to 20% of the newly synthesized CtsD is transported in ML III fibroblasts in an M6P-dependent manner. By direct sequencing a novel homozygous mutation, c.347_349delACA (p.Asn116del), was identified affecting a potential N-linked glycosylation site. Western blot analysis of extracts from control fibroblasts detect a 97 kDa glycosylated dimer whereas ML III cells contain a GNPTAG dimer of reduced molecular mass. These data suggest that the loss of the used glycosylation site in the gamma subunit may affect the intracellular localization of GNPTAG and the overall efficiency of M6P formation.

The Stuve-Wiedemann syndrome (SWS) is a congenital bone dysplasia characterized by camptodactyly with ulnar deviation and congenital bowing of the long bones. Affected patients present with respiratory difficulties in the neonatal period or later and recurrent episodes of hyperthermia. The typical radiological findings are bowing of the long bones of the lower limbs, wide metaphyses with decreased density, and abnormal trabecular pattern. Generally, respiratory insufficiency and hyperthermia are reported to be the cause of death. We report on two sibs with SWS, who died from severe pulmonary hypertension with pulmonary artery wall abnormality. We suggest a common pathophysiological process, which could explain the cardiovascular findings that we observed immediately after birth in the two affected sibs. We hypothesize that the severe pulmonary hypertension due to the arterial wall abnormality could explain the neonatal death of these two children.

Early infantile Krabbe disease is relatively frequent in the Muslim-Arab population in Israel. It can be easily diagnosed when it presents with the classic clinical picture characterized by central nervous system manifestations of spasticity, irritability, motor regression and seizures associated with a positive family history. We studied eight children diagnosed with Krabbe disease. In two of these children (25%), peripheral neuropathy was the single initial symptom and the only neurologic finding noted for a period of months. In these patients, diagnosis of Krabbe's disease was delayed and established only 9-11 months after the initial symptoms. In two other children with "classical picture" Krabbe disease, areflexia was noted on admission. The occurrence of peripheral neuropathy as an initial symptom in early infantile Krabbe disease may be underestimated. Krabbe disease should be considered in the differential diagnosis of early infantile peripheral neuropathy. Early diagnosis of affected children might be important for genetic counseling for families at risk.

Objectives Mucolipidosis IIIC (MLIIIC) is a rare autosomal recessive lysosomal storage disease resulting from defective mannose 6-phosphate-dependent lysosomal enzyme trafficking; mutations of the γ subunit of N-acetylglucosamine-1 phosphotransferase (GINAcPT) were recently found to cause its pathogenesis. We report here for the first time prenatal diagnosis (PND) for MLIIIC by means of chorionic villous sampling (CVS). Methods and Results A fetus in a large Bedouin-Moslem family was found to be homozygous for the founder haplotype and the mutational SSCP pattern of MLIIIC. The diagnosis was confirmed by markedly reduced lysosomal enzyme activities in cultured chorionic villi. The molecular identification of the disease-causing mutation in this large Bedouin-Moslem kindred permitted, for the first time, identification of carriers and couples at risk. Conclusions The feasibility of early PND for a progressive disabling disease is important for its prevention. Nevertheless, the feasibility of PND raises a serious dilemma since affected individuals might have a variable phenotype and the disease is progressive and non-lethal. In addition, religious and social constraints are important factors to be taken into consideration in the genetic counseling of couples at risk. Copyright © 2003 John Wiley & Sons, Ltd.

The recent discoveries of genes involved in deafness open new options for families and individuals with hearing loss. Our aim was to learn if parents of children with hearing loss will benefit from these new possibilities. A total of 139 parents answered questionnaires aimed at evaluating their intentions as well as their reasons to opt for or against genetic testing and prenatal diagnosis for hearing loss. A very high interest (87%) in genetic testing was found among Israeli Jewish parents of deaf and hard-of-hearing children. Although the Jewish population in Israel is very diverse in its religious beliefs, this high interest was similar across all religious sectors (secular, traditional, orthodox, and ultraorthodox); however, some of the reasons for undertaking such a test were very different between them. Reasons related to family planning and prenatal diagnosis were significantly less important to parents from the ultraorthodox sector, but the possibility to utilize genetic testing for matchmaking the children with hearing loss and their hearing siblings was an important factor in motivating them to undertake the test. Parents from all religious sectors wished testing would shed light on the cause of the hearing loss. We conclude that genetic testing would be welcomed by a wide range of communities, including those that usually do not apply for genetic counseling and testing, if it is offered in accordance with their cultural norms and beliefs.

Congenital cardiac defects such as peripheral pulmonary stenosis are well described in Alagille syndrome (AGS), which is transmitted in an autosomal dominant inheritance. Haploinsufficiency of the Jagged1 (JAG1) gene has been shown to cause AGS. Abdominal coarctation is an uncommon vascular congenital anomaly which has been described only three times in AGS. Recently, expression of the Jagged1 gene has been found in the developing heart and in multiple associated vascular structures, including the descending aorta. Mutation analysis of the Jagged1 gene in this fourth reported patient with coarctation of the abdominal aorta in AGS and right subclavian stenosis identified a mutation deletion (1485 Del CT). This agrees with the Jagged1 expression studies and suggests that coarctation of aorta may be a component of AGS.

The ductus venosus connects the portal and umbilical veins with the inferior vena cava and acts as a sphincter to protect the fetus from placental overcirculation. Its absence usually causes hydrops fetalis and is associated with high mortality rate, chromosomal anomalies and congenital malformations. In this condition, the umbilical vein almost always drains directly into right-sided structures such as inferior vena cava or right atrium. We reviewed the literature and describe the first case of a fetus with absent ductus venosus and direct connection of the umbilical vein to the coronary sinus.

To the Editor: Gaucher disease (GD) results from the deficiency of the lysosomal enzyme glucocerebrosidase. The phenotypes of patients with GD have been divided into three types, based on the presence and rate of progression of the neurologic manifestations. Both types 2 (GD2) and 3 (GD3) affect the central nervous system (CNS), but exhibit differing rates of neurological deterioration. Patients with GD2, the acute neuropathic form, present with symptoms either prenatally or during infancy, and all die before the age of 2 years, while GD3, the sub-acute neuropathic form, has a more protracted course. The three clinical forms are pan-ethnic in occurrence. The incidences of GD2 and GD3 in the general population are about 1 in 500,000 and 1 in 50,000 respectively [1]. We describe two Palestinian patients, one from Gaza and one from Jenin, which are two separate cities within the Palestinian Authority (PA) territories. They were evaluated at two different medical centers in Israel, both of which are tertiary centers for GD. Both patients had GD2 and both were found to be homozygous for the same novel mutation in the GBA gene, F331S. Patient 1, an 8-month-old male infant, was evaluated for severe failure to thrive (FTT) and hepatosplenomegaly. He was microcephalic and regression in his developmental milestones was reported. He was the second child born to first-degree cousin parents of Muslim Arab origin, resident in Jenin. Their first child is a healthy boy, now aged 5 years. The proband began to exhibit neurologic deterioration at age of 3 months, when he developed opisthotonus, and by 8 months he was hypotonic with no eye contact. He had head lag, severe strabismus, and was not able to sit. At 8 months his weight was 6.5 kg (−4 SD), head circumference 40.5 cm (−4 SD) and length 64 cm (−3 SD). The abdomen was distended with liver and spleen palpable 6 cm and 8 cm respectively below the costal margin. Both skeletal survey and brain magnetic resonance imaging (MRI) were reported as normal. The lymphocyte beta-glucosidase level was 4 nmoles/mg protein/h (controls were 31 and 26), hemoglobin level was 10.3 g/dl, WBC 8290 m3, and platelets 182,000. He died at home at age of one year. Patient 2, a 7-month old boy, was evaluated for FTT, massive hepatosplenomegaly and severe developmental delay. He was the seventh child born to first-degree cousin Muslim Arab parents from Gaza. They have four healthy children as well as two previous affected children, a boy and a girl with a similar clinical picture, both of whom died at the age of 11 months. Evaluation of one of the proband’s affected siblings revealed a beta glucosidase level of 0.367 nmoles/mg protein/h (controls were 3.3-8.15), an increased chitotriosidase level of 22,641 mmol/ml/h, and mild brain atrophy on brain MRI. Physical examination of the proband at the age of 7 months revealed an irritable infant with significant FTT. His weight was 4868 gr (−4SD), and he reacted to noises but was unable to track. Neurological evaluation revealed hypertonicity of all four limbs and a constantly arched back. He had a grade 2/6 systolic murmur and hepatosplenomegaly — liver and spleen were both 5 cm below the costal margin. His blood count revealed a hemoglobin level of 8.1 gr/dl, leukocyte count 10,600/mm3 (25% neutrophils, 64% lymphocytes), platelets 124,000/mm3, and acid phosphatase 36u/l (normal up to 10). Beta glucosidase was 4 nmol/h/ mg (deficient control 2 and normal control 19). An abdominal ultrasound showed an enlarged liver with increased echogenicity (10.3 cm span) and an enlarged spleen (8.9 cm). MRI showed prominent cortical sulci and fissures indicating mild brain atrophy and delayed myelination. The child died several weeks later. Genomic DNA was extracted from lymphocyte samples, including flanking intronic sequences and a 1 kb segment at the 5′ promoter region, were amplified using primers complementary to the functional gene but not the pseudogene. PCR products were sequenced with primers specific for each exon [2]. Full sequencing of the GBA gene revealed homozygosity for the F331S (c.1109 TNC) mutation in both probands. The parents in each case were found to be F331S carriers. No other mutations were identified. This novel mutation was not seen in over 500 GBA alleles sequenced in controls and patients with GD. While it is not known whether the two families were related, the relative proximity of their origins suggests the possibility of a founder mutation in this population. This mutation changes phenylalanine, an aromatic amino acid, to serine, a polar uncharged amino acid. This residue is conserved in 19 mammalian species [3] and analysis with Maestro software (Schrodinger, Inc., New York) predicts this mutation to be pathogenic. F331S is located in exon 8 of GBA, a region involved in the catalytic activity of the enzyme [4], and is partially exposed at the surface. It makes hydrophobic contact with L296, so the serine mutant would disrupt this contact, which could render the mutant protein less stable. In summary, from this report and the literature [5], F331S appears to be a severe mutation which, in the homozygous state, leads to a non-perinatal lethal form of GD2. As is known, ERT treatment has been shown not to be beneficial in GD2 [6-8], so this was not offered and the children received supportive care on their return to their homes in the PA territories. We received the molecular analysis results after both families returned home, but despite repeat invitations for genetic counseling they were lost for follow up. Therefore, unfortunately, we could not enable these families to undergo prenatal diagnosis in future pregnancies. The prevalence of GD2 in the Palestinian population is not reported in the literature. In view of these two patients, population screening in the Palestinian community is recommended to determine the prevalence of carriers of this mutation and to establish the need for genetic counseling and prenatal diagnosis.

Correction to: European Journal of Human Genetics advance online publication, 15 January 2014; doi:10.1038/ejhg.2013.288 After the above article had been published online, it was brought to the authors’ attention that Figure 1 contained an image for which the patient had not given his consent for publication.

The gene MCOLN1 is mutated in Mucolipidosis type IV (MLIV), a neurodegenerative, recessive, lysosomal storage disorder. The disease is found in relatively high frequency among Ashkenazi Jews due to two founder mutations that comprise 95% of the MLIV alleles in this population [Bargal et al., 2000]. In this report we complete the mutation analysis of Jewish and non-Jewish MLIV patients whose DNA were available to us. Four novel mutations were identified in the MCOLN1 gene of severely affected patients: two missense, T232P and F465L; a nonsense, R322X; and an 11-bp insertion in exon 12. The nonsense mutation (R322X) was identified in two unrelated patients with different haplotypes in the MCOLN1 chromosomal region, indicating a mutation hotspot in this CpG site. An in-frame deletion (F408del) was identified in a patient with unusual mild psychomotor retardation. The frequency of MLIV in the general Jewish Ashkenazi population was estimated in a sample of 2,000 anonymous, unrelated individuals assayed for the two founder mutations. This analysis indicated a heterozygotes frequency of about 1/100. A preferred nucleotide numbering system for MCOLN1 mutations is presented and the issue of a screening program for the detection of high-risk families in the Jewish Ashkenazi population is discussed. Hum Mutat 17:397–402, 2001. © 2001 Wiley-Liss, Inc.

Bardet–Biedl syndrome (BBS, MIM 209900) is a heterogeneous autosomal recessive disorder characterized by obesity, pigmentary retinopathy, polydactyly, renal malformations, mental retardation, and hypogenitalism1,2,3,4. The disorder is also associated with diabetes mellitus, hypertension, and congenital heart disease4,5,6. Six distinct BBS loci map to 11q13 (BBS1), 16q21 (BBS2), 3p13–p12 (BBS3), 15q22.3–q23 (BBS4), 2q31 (BBS5), and 20p12 (BBS6)7,8,9,10,11,12,13. Although BBS is rare in the general population (

First described by Maroteaux and Lamy in 1966,1 mucolipidosis III (ML III) or pseudo-Hurler polydystrophy (MIM 252600; Online Mendelian Inheritance in Man (OMIM), McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD), 2000; http://www.ncbi.nlm.nih.gov/omim/) is a rare autosomal recessive condition resembling Hurler syndrome with no organomegaly or mucopolysacchariduria. Clinical manifestations are variable and progress into adulthood. Bone involvement is slowly progressive and bone pain and disability due to destruction of hip joints are the most frequent and debilitating symptoms. Clinical symptoms include stiffness of the fingers and shoulders, claw hand deformity, short stature, and scoliosis. Mild coarsening of the face with corneal clouding, mild retinopathy, astigmatism, and cardiac valve involvement have also been reported. The radiological findings include moderate to severe dysostosis multiplex with vertebral changes.2 ML III is due to the abnormal trafficking and subcellular localisation of lysosomal enzymes.3–5 Newly synthesised lysosomal enzymes are secreted into the extracellular medium instead of being properly targeted to the lysosomes because they lack a mannose 6-phosphate receptor recognition marker.3,4 The UDP -N- acetylglucosamine-1-phosphotransferase enzyme activity is defective in ML III6 and three complementation groups (A, B, C) have been reported suggesting genetic heterogeneity.7 ML III complementation group C (MIM 252605) is characterised by deficient enzyme activity when assayed with lysosomal glycoproteins as acceptors, but normal activity when assayed with the simple acceptor, α-methylmannoside.6,8 In 1996, Bao et al 9 showed that UDP -N- acetylglucosamine-1-phosphotransferase is a multimeric enzyme made up of three different subunits.9 We have previously ascribed ML III type C to mutations in the UDP -N- acetylglucosamine-1-phosphotransferase gamma subunit gene (GNPTAG) on chromosome 16p.10 Here, we report the genomic structure of this gene and its …

The spondylo-meta-epiphyseal dysplasia [SMED] short limb-hand type [SMED-SL] is a rare autosomal-recessive disease, first reported by Borochowitz et al. in 1993.(1) Since then, 14 affected patients have been reported.(2-5) We diagnosed 6 patients from 5 different consanguineous Arab Muslim families from the Jerusalem area with SMED-SL. Additionally, we studied two patients from Algerian and Pakistani ancestry and the parents of the first Jewish patients reported.(1) Using a homozygosity mapping strategy, we located a candidate region on chromosome 1q23 spanning 2.4 Mb. The position of the Discoidin Domain Receptor 2 (DDR2) gene within the candidate region and the similarity of the ddr2 knockout mouse to the SMED patients' phenotype prompted us to study this gene(6). We identified three missense mutations c.2254 C > T [R752C], c. 2177 T > G [I726R], c.2138C > T [T713I] and one splice site mutation [IVS17+1g > a] in the conserved sequence encoding the tyrosine kinase domain of the DDR2 gene. The results of this study will permit an accurate early prenatal diagnosis and carrier screening for families at risk.