Jeune asphyxiating thoracic dystrophy and short‐rib polydactyly type III (Verma‐Naumoff) are variants of the same disorder

Jeune syndrome (JS) and short‐rib polydactyly syndrome type III (SRP type III) are autosomal recessive disorders characterized by short ribs and polydactyly. They are distinguished from each other by the more severe radiological and histological bone findings as well as the occurrence of facial anomalies, ambiguous genitalia, and occasionally, cloacal abnormalities in SRP type III. We present a family in which two children have mild JS and one has SRP type III as evidence that JS and SRP type III are variants of the same disorder. The intrafamilial variability may reflect the effects of modifying loci on gene expression. Am. J. Med. Genet. 90:310–314, 2000. © 2000 Wiley‐Liss, Inc.     

Skeletal histopathology in fetuses with chondroectodermal dysplasia (Ellis-van creveld syndrome)

Chondroectodermal dysplasia (CED) is an uncommon autosomal recessive disorder and one of the short rib polydactyly syndromes (SRPS). It is characterized by acromelic and mesomelic shortness of limbs, postaxial polydactyly, small chest, ectodermal dysplasia, and in many cases, congenital heart defects. Controversy exists over possible changes in the growth plate. With the advent of ultrasonographic examination, increasing numbers of fetuses with osteochondrodysplasias are examined by pathologists. Since histopathologic examination of the skeletal system is useful in defining various osteochondrodysplasias and it has not been described in the fetus with CED, we herein describe 3 cases of fetal CED with emphasis on skeletal histopathology. All 3 pregnancies were terminated at 22–23 weeks because of ultrasonographic demonstration of short limbs and growth retardation. Radiologically, each fetus had acromelic and mesomelic shortness of long bones with smooth round metaphyses, vertically short iliac bones, short ribs and normal vertebrae. These findings are similar to those described in the larger newborn infant with CED. Histopathologically, the cartilage of the long bones showed chondrocytic disorganization in the physeal growth zone. The findings are dissimilar to those of larger infants and older children in whom chondrocytic columnization has been seen in the central physis and disorganization in peripheral physis. Furthermore, a variable degree of chondrocytic disorganization was also seen in the central physeal growth zone of vertebrae in these fetuses. Other findings noted at fetopsy were: polydactyly in all 3 cases, congenital heart defect in 2 and an abnormal frenulum in one case. The foregoing phenotypic and radiographic manifestations and skeletal histopathology help separate CED from other SRPS. © 1993 Wiley-Liss, Inc.     

Biallelic mutations in DYNC2LI1 are a rare cause of Ellis‐van Creveld syndrome

Ellis‐van Creveld syndrome (EvC) is a chondral and ectodermal dysplasia caused by biallelic mutations in the EVC, EVC2 and WDR35 genes. A proportion of cases with clinical diagnosis of EvC, however, do not carry mutations in these genes. To identify the genetic cause of EvC in a cohort of mutation‐negative patients, exome sequencing was undertaken in a family with 3 affected members, and mutation scanning of a panel of clinically and functionally relevant genes was performed in 24 additional subjects with features fitting/overlapping EvC. Compound heterozygosity for the c.2T>C (p.Met1?) and c.662C>T (p.Thr221Ile) variants in DYNC2LI1, which encodes a component of the intraflagellar transport‐related dynein‐2 complex previously found mutated in other short‐rib thoracic dysplasias, was identified in the 3 affected members of the first family. Targeted resequencing detected compound heterozygosity for the same missense variant and a truncating change (p.Val141*) in 2 siblings with EvC from a second family, while a newborn with a more severe phenotype carried 2 DYNC2LI1 truncating variants. Our findings indicate that DYNC2LI1 mutations are associated with a wider clinical spectrum than previously appreciated, including EvC, with the severity of the phenotype likely depending on the extent of defective DYNC2LI1 function.     

Short-rib–polydactyly syndrome type Verma-Naumoff–Le Marec in a fetus with histological hallmarks of type Saldino-Noonan but lacking internal organ abnormalities

Up to seven short-rib–polydactyly (SRP) syndromes have been identified so far with marked clinical and pathological overlap. We describe a 32-week-old, nonhydropic male fetus with thoracic “dysplasia,” short limbs, and unilateral postaxial polydactyly. All internal organs were normally developed, including the central nervous system. The external genitalia were unambiguously male, in accordance with a 46,XY karyotype. Radiological signs most closely resembled those of SRP, type Le Marec, though histology of the femoral physeal growth zone was consistent with the Saldino-Noonan type. The remarkable lack of visceral anomalies in conjunction with the radiological and histological findings further adds to the phenotypic spectrum of the SRP syndromes. The histological analysis in this case supports a close relationship between types Saldino-Noonan and Verma-Naumoff–Le Marec. Am. J. Med. Genet. 80:281–285, 1998. © 1998 Wiley-Liss, Inc.     

Novel Mutations in the DYNC1H1 Tail Domain Refine the Genetic and Clinical Spectrum of Dyneinopathies

The heavy chain 1 of cytoplasmic dynein (DYNC1H1) is responsible for movement of the motor complex along microtubules and recruitment of dynein components. Mutations in DYNC1H1 are associated with spinal muscular atrophy (SMA), hereditary motor and sensory neuropathy (HMSN), cortical malformations, or a combination of these. Combining linkage analysis and whole‐exome sequencing, we identified a novel dominant defect in the DYNC1H1 tail domain (c.1792C>T, p.Arg598Cys) causing axonal HMSN. Mutation analysis of the tail region in 355 patients identified a de novo mutation (c.791G>T, p.Arg264Leu) in an isolated SMA patient. Her phenotype was more severe than previously described, characterized by multiple congenital contractures and delayed motor milestones, without brain malformations. The mutations in DYNC1H1 increase the interaction with its adaptor BICD2. This relates to previous studies on BICD2 mutations causing a highly similar phenotype. Our findings broaden the genetic heterogeneity and refine the clinical spectrum of DYNC1H1, and have implications for molecular diagnostics of motor neuron diseases.     

Whole exome sequencing is an efficient,sensitive and specific method for determining the genetic cause of short‐rib thoracic dystrophies

Short‐rib thoracic dystrophies (SRTDs) are congenital disorders due to defects in primary cilium function. SRTDs are recessively inherited with mutations identified in 14 genes to date (comprising 398 exons). Conventional mutation detection (usually by iterative Sanger sequencing) is inefficient and expensive, and often not undertaken. Whole exome massive parallel sequencing has been used to identify new genes for SRTD (WDR34, WDR60 and IFT172); however, the clinical utility of whole exome sequencing (WES) has not been established. WES was performed in 11 individuals with SRTDs. Compound heterozygous or homozygous mutations were identified in six confirmed SRTD genes in 10 individuals (IFT172, DYNC2H1, TTC21B, WDR60, WDR34 and NEK1), giving overall sensitivity of 90.9%. WES data from 993 unaffected individuals sequenced using similar technology showed two individuals with rare (minor allele frequency <0.005) compound heterozygous variants of unknown significance in SRTD genes (specificity >99%). Costs for consumables, laboratory processing and bioinformatic analysis were <AU$850 per sample. WES is sensitive, specific, efficient and cost‐effective for mutation screening as well as gene discovery in SRTDs and can be considered a first‐line methodology for mutation identification in affected individuals.     

Short rib syndrome—Beemer type in sibs

The short rib (polydactyly) syndrome Beemer type is a rare lethal osteochondrodysplasia characterized clinically by short limbs, median cleft upper lip and palate, narrow thorax, and protuberant abdomen, and radiologically by short ribs, short and bowed long bones, and mild platyspondyly. Two affected female sibs are described, one having a preaxial polydactyly of the feet. The differentiation with the short rib syndrome Majewski type relies mainly on the radiological appearance of the tibia. Molecular biology may eventually prove whether the 2 conditions are truly separate entities or not.     

Prenatal diagnosis of short rib (polydactyly) syndrome with situs inversus

We present a case of short rib (polydactyly) syndrome in which the diagnosis was made prenatally by ultrasound examination. The more specific diagnosis of short rib (polydactyly) syndrome type III was made on the basis of findings on radiographs obtained at birth. The sonographic and radiographic features are discussed. The patient had complete situs inversus and hypospadias. The former was reported in one other case of type III and the later has not been previously reported in this entity. © 1992 Wiley-Liss, Inc.     

Jeune syndrome with tongue lobulation and preaxial polydactyly,and Jeune syndrome with situs inversus and asplenia: Compound heterozygosity Jeune-Mohr and Jeune-Ivemark?

We report on a male infant with internal hydrocephalus, absence of corpus callosum, papillomas and lobulation of the tongue, notches of the alveolar ridges, short ribs, dysplastic pelvis, hypospadias, short limbs with bowed long tubular bones and postaxial polydactyly of hands, and preaxial polydactyly in one foot. Radiologically this case shares manifestations with Jeune syndrome; the tongue lobulation and the preaxial polydactyly are similar to findings in Mohr syndrome, or short-rib polydactyly syndrome (SRPS), type Majewski. In addition, a female newborn presented with manifestations of Jeune and Ivemark syndromes. One explanation for this overlap may be compound heterozygosity for these syndromes. © 1996 Wiley-Liss, Inc.     

Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies

Defects in the biosynthesis and/or function of primary cilia cause a spectrum of disorders collectively referred to as ciliopathies. A subset of these disorders is distinguished by profound abnormalities of the skeleton that include a long narrow chest with markedly short ribs, extremely short limbs, and polydactyly. These include the perinatal lethal short‐rib polydactyly syndromes (SRPS) and the less severe asphyxiating thoracic dystrophy (ATD), Ellis–van Creveld (EVC) syndrome, and cranioectodermal dysplasia (CED) phenotypes. To identify new genes and define the spectrum of mutations in the skeletal ciliopathies, we analyzed 152 unrelated families with SRPS, ATD, and EVC. Causal variants were discovered in 14 genes in 120 families, including one newly associated gene and two genes previously associated with other ciliopathies. These three genes encode components of three different ciliary complexes; FUZ, which encodes a planar cell polarity complex molecule; TRAF3IP1, which encodes an anterograde ciliary transport protein; and LBR, which encodes a nuclear membrane protein with sterol reductase activity. The results established the molecular basis of SRPS type IV, in which mutations were identified in four different ciliary genes. The data provide systematic insight regarding the genotypes associated with a large cohort of these genetically heterogeneous phenotypes and identified new ciliary components required for normal skeletal development.     

Noonan syndrome and neurofibromatosis type I in a family with a novel mutation in NF1

Noonan syndrome (NS) and neurofibromatosis type I (NF1) belong to a group of clinically related disorders that share a common pathogenesis, dysregulation of the RAS‐MAPK pathway. NS is characterized by short stature, heart defect, pectus deformity and facial dysmorphism, whereas skin manifestations, skeletal defects, Lisch nodules and neurofibromas are characteristic of NF1. Both disorders display considerable clinical variability. Features of NS have been observed in individuals with NF1 –a condition known as neurofibromatosis–Noonan syndrome (NFNS). The major gene causing NFNS is NF1. Rarely, a mutation in PTPN11 in addition to an NF1 mutation is present. We present the clinical and molecular characterization of a family displaying features of both NS and NF1, with complete absence of neurofibromas. To investigate the etiology of the phenotype, mutational analysis of NF1 was conducted, revealing a novel missense mutation in exon 24, p.L1390F, affecting the GAP‐domain. Additional RAS‐MAPK pathway genes were examined, but no additional mutations were identified. We confirm that NF1 mutations are involved in the etiology of NFNS. Furthermore, based on our results and previous studies we suggest that evaluation of the GAP‐domain of NF1 should be prioritized in NFNS.     

Loss of function IFT27 variants associated with an unclassified lethal fetal ciliopathy with renal agenesis

Ciliopathies comprise a group of clinically heterogeneous and overlapping disorders with a wide spectrum of phenotypes ranging from prenatal lethality to adult‐onset disorders. Pathogenic variants in more than 100 ciliary protein‐encoding genes have been described, most notably those involved in intraflagellar transport (IFT) which comprises two protein complexes, responsible for retrograde (IFT‐A) and anterograde transport (IFT‐B). Here we describe a fetus with an unclassified severe ciliopathy phenotype including short ribs, polydactyly, bilateral renal agenesis, and imperforate anus, with compound heterozygosity for c.118_125del, p.(Thr40Glyfs*11) and a c.352 +1G > T in IFT27, which encodes a small GTPase component of the IFT‐B complex. We conclude that bilateral renal agenesis is a rare feature of this severe ciliopathy and this report highlights the phenotypic overlap of Pallister–Hall syndrome and ciliopathies. The phenotype in patients with IFT27 gene variants is wide ranging from Bardet–Biedl syndrome to a lethal phenotype.     

Early prenatal diagnosis of polycystic pancreas with narrow thorax and short limb dwarfism

We describe the ultrasound findings of polycystic pancreas with short rib dwarfism in the early second trimester. Radiologic, morphologic, and histologic examination after pregnancy termination confirmed the findings and also disclosed dysplastic kidneys. The skeletal anomalies are similar to those in Verma Naumoff type of short rib polydactyly, but the extraskeletal malformations have never been reported before in this syndrome. © 1994 Wiley-Liss, Inc.     

Novel Dynein DYNC1H1 Neck and Motor Domain Mutations Link Distal Spinal Muscular Atrophy and Abnormal Cortical Development

DYNC1H1 encodes the heavy chain of cytoplasmic dynein 1, a motor protein complex implicated in retrograde axonal transport, neuronal migration, and other intracellular motility functions. Mutations in DYNC1H1 have been described in autosomal‐dominant Charcot–Marie–Tooth type 2 and in families with distal spinal muscular atrophy (SMA) predominantly affecting the legs (SMA‐LED). Recently, defects of cytoplasmic dynein 1 were also associated with a form of mental retardation and neuronal migration disorders. Here, we describe two unrelated patients presenting a combined phenotype of congenital motor neuron disease associated with focal areas of cortical malformation. In each patient, we identified a novel de novo mutation in DYNC1H1: c.3581A>G (p.Gln1194Arg) in one case and c.9142G>A (p.Glu3048Lys) in the other. The mutations lie in different domains of the dynein heavy chain, and are deleterious to protein function as indicated by assays for Golgi recovery after nocodazole washout in patient fibroblasts. Our results expand the set of pathological mutations in DYNC1H1, reinforce the role of cytoplasmic dynein in disorders of neuronal migration, and provide evidence for a syndrome including spinal nerve degeneration and brain developmental problems.     

Mutations in IFT80 cause SRPS Type IV. Report of two families and review

We report novel causative mutations in the IFT80 gene identified in four fetuses from two unrelated families with Beemer‐Langer syndrome (BLS) or BLS‐like phenotypes. We discuss the implication of the IFT80 gene in ciliopathies, and its diagnostic value for BLS among other SRPS.     

Short rib-polydactyly syndrome,type 3 with chondrocytic inclusions: Report of a case and review of the literature

A newborn with severely shortened ribs, short limbs, and postaxial polydactyly died shortly after birth. Postmortem roentgenograms established the diagnosis of type 3 short rib-polydactyly (SRP) syndrome as described by Naumoff and associates. Histopathologic study showed the chondrocytes to contain previously undescribed cytoplasmic inclusion bodies that were PAS-positive and diastase-resistant. The material appeared by staining reactions to be a glycoprotein that was seen electron microscopically to accumulate within dilated cisterns of rough endoplasmic reticulum. Similar cytoplasmic inclusions have not been seen in other short rib-polydactyly syndromes, including SRP types 1 and 2, Jeune syndrome, and Ellis-van Creveld syndrome. It is often difficult to differentiate cases of type 3 and type 1 (Saldino-Noonan) syndrome, and in the past the diagnosis has sometimes been confused. A review of previously reported cases showed that type 3 syndrome rarely (1 in 13) had cloacal developmental abnormalities, which are invariably present in patients with type 1 syndrome. Type 3 is also associated with a lower incidence of congenital heart disease, and cardiac malformations, when present, differ from those associated with type 1 syndrome. Both type 3 and type 1 SRP syndromes are transmitted in autosomal recessive fashion. Type 3 SRP syndrome has had an equal sex distribution, although type 1 has so far been reported to occur only in girls. Further investigation with additional patients is necessary to verify the above preliminary findings.     

Further delineation of the Beemer–Langer syndrome using concordance rates in affected sibs

Six familial cases of the Beemer–Langer syndrome (BLS) were analyzed to further elucidate the spectrum and frequency of anomalies observed in this disorder. Preaxial polydactyly was found in 3/6 affected sibs, and, therefore, its frequency previously may have been underestimated. Some patients, described as infants affected with the Majewski syndrome (MS) or “atypical” short rib-poly-dactyly conditions, may indeed have BLS. A high frequency of brain defects (16/26) and cleft tongue, oral frenula, and/or natal teeth (13/29) widens the list of typical findings in this syndrome. The specific type of tibial defect seems to be the most important discrimination of the MS and the BLS. © 1994 Wiley-Liss, Inc.     

Ehlers-Danlos syndrome type VIIA and VIIB result from splice-junction mutations or genomic deletions that involve exon 6 in the COL1A1 and COL1A2 genes of type I collagen

Ehlers-Danlos syndrome (EDS) type VII results from defects in the conversion of type I procollagen to collagen as a consequence of mutations in the substrate that alter the protease cleavage site (EDS type VIIA and VIIB) or in the protease itself (EDS type VIIC). We identified seven additional families in which EDS type VII is either dominantly inherited (one family with EDS type VIIB) or due to new dominant mutations (one family with EDS type VIIA and five families with EDS type VIIB). In six families, the mutations alter the consensus splice junctions, and, in the seventh family, the exon is deleted entirely. The COL1A1 mutation produced the most severe phenotypic effects, whereas those in the COL1A2 gene, regardless of the location or effect, produced congenital hip dislocation and other joint instability that was sometimes very marked. Fractures are seen in some people with EDS type VII, consistent with alterations in mineral deposition on collagen fibrils in bony tissues. These new findings expand the array of mutations known to cause EDS type VII and provide insight into genotype/phenotype relationships in these genes. Am. J. Med. Genet. 72:94–105, 1997. © 1997 Wiley-Liss, Inc.     

Mutation Update for Kabuki Syndrome Genes KMT2D and KDM6A and Further Delineation of X‐Linked Kabuki Syndrome Subtype 2

Kabuki syndrome (KS) is a rare but recognizable condition that consists of a characteristic face, short stature, various organ malformations, and a variable degree of intellectual disability. Mutations in KMT2D have been identified as the main cause for KS, whereas mutations in KDM6A are a much less frequent cause. Here, we report a mutation screening in a case series of 347 unpublished patients, in which we identified 12 novel KDM6A mutations (KS type 2) and 208 mutations in KMT2D (KS type 1), 132 of them novel. Two of the KDM6A mutations were maternally inherited and nine were shown to be de novo. We give an up‐to‐date overview of all published mutations for the two KS genes and point out possible mutation hot spots and strategies for molecular genetic testing. We also report the clinical details for 11 patients with KS type 2, summarize the published clinical information, specifically with a focus on the less well‐defined X‐linked KS type 2, and comment on phenotype–genotype correlations as well as sex‐specific phenotypic differences. Finally, we also discuss a possible role of KDM6A in Kabuki‐like Turner syndrome and report a mutation screening of KDM6C (UTY) in male KS patients.