Pronounced short stature in a girl with tricho-rhino-phalangeal syndrome II (TRPS II, Langer-Giedion syndrome) and growth hormone deficiency.

We report on a 10-year-old girl with tricho-rhino-phalangeal syndrome type II (TRPS II) and pronounced short stature (-4.8 SD). The patient has an interstitial chromosome 8q24.1 deletion of 12-15 Mb. The deletion spans all genes from CSMD3 to at least ANXA13 including the TRPS1 and EXT1 genes, which are responsible for the TRPS II phenotype. In addition to the features of TRPS II, the patient had growth hormone (GH) deficiency with diminished response in three stimulation tests. Therapy with 0.2 mg GH/kg/week led to an increase of growth velocity from 2.5 to 6.6 cm/year. To our knowledge, such a combination of TRPS II and GH deficiency has not yet been described.

RMRP gene sequence analysis confirms a cartilage-hair hypoplasia variant with only skeletal manifestations and reveals a high density of single-nucleotide polymorphisms.

Mutations in the RMRP gene that codes for an RNA subunit of the MRP RNAse complex are the cause of cartilage-hair hypoplasia (CHH; MIM 250250). We tested the hypothesis that recessive metaphyseal dysplasia without hypotrichosis (M1M 250460), a disorder presenting with short stature and metaphyseal dysplasia similar to CHH, but lacking hair anomalies, immunodeficiency and other extra skeletal features, might be allelic to CHH. We identified four mutation-carrying alleles segregating with the skeletal phenotype in two unrelated boys and their parents. One allele carried the common Finnish mutation +70A--> G; the remaining three carried +195C--> T, +238C--> T, and dupAAGCTGAGGACG at -2. Sequencing 120 alleles from a control group revealed an unusually high density of single-nucleotide polymorphisms in and around the RMRP gene: the biological significance of this finding is unclear. We conclude that recessive metaphyseal dysplasia without hypotrichosis is a variant of CHH, manifesting only as short stature and metaphyseal dysplasia. Precise diagnosis of this form of metaphyseal dysplasia is not without importance because of recessive inheritance with corresponding recurrence risk, as well as because of potential complications such as anaemia, susceptibility to infections and the increased likelihood of developing cancer. The short stature and metaphyseal changes associated with cone-shaped epiphyses of the hands should raise the diagnostic possibility of a CHH-related disorder that can then be confirmed by mutation analysis.

Phalangeal cone-shaped epiphyses of the hand: their natural history, diagnostic sensitivity, and specificity in cartilage hair hypoplasia and the trichorhinophalangeal syndromes I and II.

Phalangeal cone-shaped epiphyses are an ideal object for the radiologist to study with temporal reasoning, to examine their shape, diagnostic usefulness, natural history and effect on pathophysiology. Radiographs of the hands of 60 patients with cartilage hair hypoplasia (CHH), 69 with trichorhinophalangeal syndrome I (TRP I) and 11 with TRP II were examined, including 26 longitudinal observations. The early phases of cone development were recorded. In CHH a characteristic mesophalangeal type of cone in 42/47 patients of the "Age Suitable for Classification" (ASC) was detected. All 46 TRP I and 9 TRP II patients in the ASC had the previously described mesophalangeal cone type 12. However, 1/4 of these TRP I and all TRP II cases presented a milder variant of type 12: type 12 A. A complex sequence of secondary changes in the proximal interphalangeal joints in TRP I leading eventually to subluxation was recorded. It can be concluded that in the ASC the cones described are highly sensitive but not specific diagnostic indicators. In infancy and early childhood, other phalangeal changes were found, which may be of diagnostic help.

Heterozygous glycine substitution in the COL11A2 gene in the original patient with the Weissenbacher-Zweymüller syndrome demonstrates its identity with heterozygous OSMED (nonocular Stickler syndrome).

The original patient with the Weissenbacher-Zweymüller syndrome was analyzed for mutations in two candidate genes expressed in cartilage (COL2A1 and COL11A2). No mutations were found in the COL2A1 gene but the COL11A2 gene contained a single-base mutation that converted a codon for an obligate glycine to a codon for glutamate at position alpha 2-955 (G955E). The results here and those published previously indicate that the Weissenbacher-Zweymüller syndrome (heterozygous OSMED), nonocular Stickler syndrome, and homozygous OSMED are all caused by mutations in the COL11A2 gene.

Clinical homogeneity of the Stüve-Wiedemann syndrome and overlap with the Schwartz-Jampel syndrome type 2.

The Stüve-Wiedemann syndrome (SWS) is a rare disorder characterized by respiratory distress, hyperthermic episodes, and early lethality and radiologically by bowing of the long bones with internal cortical thickening and large metaphyses. We report findings in 8 new patients suggesting that this syndrome is clinically homogeneous. All patients had feeding and swallowing difficulties, respiratory insufficiency, abnormal appearance, muscle hypotonia, and postnatal short stature. Recurrent episodes of unexplained fever occurred in all and were the cause of death in 6 of 8 cases. Parental consanguinity and sib recurrence suggest autosomal recessive inheritance. The clinical, radiological, and histological similarities between our patients with SWS and those with the recently delineated "neonatal" Schwartz-Jampel syndrome (SJS type 2) lead us to suggest that SWS and SJS type 2 may be a single entity.

Schwartz-Jampel syndrome type 2 and Stüve-Wiedemann syndrome: a case for "lumping".

Recent studies demonstrated the existence of a genetically distinct, usually lethal form of the Schwartz-Jampel syndrome (SJS) of myotonia and skeletal dysplasia, which we called SJS type 2. This disorder is reminiscent of another rare condition, the Stüve-Wiedemann syndrome (SWS), which comprises campomelia at birth with skeletal dysplasia, contractures, and early death. To test for possible nosologic identity between these disorders, we reviewed the literature and obtained a follow-up of the only two surviving patients, one with SJS type 2 at age 10 years and another with SWS at age 7 years. Patients reported as having either neonatal SJS or SWS presented a combination of a severe, prenatal-onset neuromuscular disorder (with congenital joint contractures, respiratory and feeding difficulties, tendency to hyperthermia, and frequent death in infancy) with a distinct campomelic-metaphyseal skeletal dysplasia. The similarity of the clinical and radiographic findings is so extensive that these disorders appear to be a single entity. The follow-up observation of an identical and unique pattern of progressive bone dysplasia in the two patients (one with SJS type 2, one with SWS) surviving beyond infancy adds to the evidence in favor of identity. The hypothesis that SWS and SJS type 2 are the same disorder should be testable by molecular methods.

Heterogeneity in Schwartz-Jampel chondrodystrophic myotonia.

UNLABELLED: The Schwartz-Jampel syndrome (SJS; chondrodystrophic myotonia; McK 255,800) is a recessively inherited condition defined by myotonia, short stature, and bone dysplasia. Genetic linkage between SJS and chromosomal region 1q36-34 has been observed in several families, but the gene has not yet been identified. We studied the clinical and radiological features in 81 patients from the literature and 5 own patients trying to identify distinct subgroups. In addition, we tested genetic linkage to the SJS locus on chromosome 1 in one family with two affected sibs. We found that a group of patients have mild skeletal changes which may be secondary consequences of myotonia, while another group of patients appear to have primary bone dysplasia with myotonia. Within this latter group, there are differences in age of manifestation, clinical course and pattern of bone changes. We tentatively isolate three different types of SJS: type 1A, usually recognized in childhood, with moderate bone dysplasia, corresponding to the original descriptions of Schwartz, Jampel and Aberfeld; type 1B, similar to type 1A but recognizable at birth, with more pronounced bone dysplasia resembling Kniest dysplasia; and type 2, manifest at birth, with increased mortality and bone dysplasia resembling Pyle disease. Genetic analysis of the family with two sibs affected by SJS type 2 showed evidence against linkage to chromosome 1p36-34. CONCLUSIONS: SJS is clinically and radiologically heterogeneous. The causes of heterogeneity are not known yet but are likely to include both different mutations at the SJS locus on chromosome 1 and the presence of a second SJS locus. A tentative clinico-radiological classification can be useful for the characterization of patients and the development of genotype-phenotype correlations.

Brachydactyly-short stature-hypertension (Bilginturan) syndrome: report on two families.

We report on two families with autosomal dominant brachydactyly of hands and feet and hypertension. All affected members of the first family had proportionate short stature. However, the propositus and the affected relatives in the second family were only short compared to unaffected relatives. The hypertension was medically responsive in all cases. The propositus in the second family had poor compliance and a striking generalized vasculopathy. All patients were of normal intelligence and had a normal facial appearance. The brachydactyly-short stature-hypertension syndrome was first reported by Bilginturan et al. [1973] in a Turkish family and the families reported by us are Caucasian and Hispanic. The gene causing this condition in the original Turkish family was recently mapped to 12p. Our report expands our existing knowledge and the ethnic diversity of this syndrome.

Metaphyseal peg in geroderma osteodysplasticum: a new genetic bone marker and a specific finding?

We describe two sibs with geroderma osteodysplasticum (GO) who, in addition to the known clinical and radiologic manifestations of the disorder, presented a metaphyseal peg indenting the epiphysis of the long bones, particularly at the knees. The peg was visible only at the age of 4 to 5 years but was invisible in infancy and following physeal closure. This may explain why this anomaly was not described in previous reports of 23 patients in 11 families with GO. The metaphyseal peg is an abnormality of bone development so far unknown to us. We speculate that it represents a primary, agedependent alteration of bone shape and hence a new genetic bone marker apparently specific to GO.

A glycine 375-to-cysteine substitution in the transmembrane domain of the fibroblast growth factor receptor-3 in a newborn with achondroplasia.

Achondroplasia, the most common form of chondrodysplasia, has been associated with mutations in the gene of the fibroblast growth factor receptor-3 (FGFR-3) on chromosome 4p. All 39 achondroplasia alleles studied so far carried point mutations which caused the same amino acid exchange, a substitution of glycine by arginine at position 380 (G380R) in the transmembrane domain of the receptor. We report on a newborn with achondroplasia who does not carry a G380R mutation but has a mutation causing substitution of a nearby glycine with a cysteine (G375C). This observation indicates allelic heterogeneity and confirms the role of mutations in the transmembrane domain of FGFR-3 in the pathogenesis of achondroplasia.

A new type of a lethal osteochondrodysplasia with angel-shaped brachyphalangy.

A hydropic stillborn female fetus of 22 weeks gestation with shortlimbed skeletal dysplasia and brachyphalangy is described. The markedly shortened phalanges of both hands had a most unusual angel-like configuration radiologically. Histological examination and comparison with a normal hand of the same gestational age revealed this appearance to be due to disturbed enchondral ossification with premature calcification of epiphyseal cartilage and thickening and outfolding of diaphyseal bone as wing-shaped appositions. Magnetic resonance imaging of the fetus demonstrated marked hyperplasia of cartilage, most impressive in the pelvis. This new type of lethal bone dysplasia may be placed in the group of metatropic dysplasias and similar disorders.

Angel-shaped phalango-epiphyseal dysplasia (ASPED): identification of a new genetic bone marker.

We describe a "new" mild malformation of the phalanx, which we call the "angel-shaped phalanx" (ASP) because of its resemblance to the little angels used for the decoration of Christmas trees. A particular middle phalangeal type of ASPs is found in a distinct variety of multiple epiphyseal dysplasia with marked retardation of bone age and severe coxarthrosis in adult life, previously reported as "hereditary peripheral dysostosis" [Bachman, 1967: Proc R Soc Med 60:21-22; Giedion, 1969: Fortschr Rontgenstr 110:507-524]. However, these authors overlooked the unique configuration of the middle phalanges. We renamed the condition "angel-shaped phalango-epiphyseal dysplasia (ASPED)", which may be transmitted in an autosomal-dominant manner. Six new patients are added, bringing the total to nine patients (two families and two isolated patients). ASPs were seen in five of six children. The ASPs grew into inconspicuous brachydactyly after physeal closure (3/3). The most important additional radiological finding is late and dysplastic development of both femoral heads (5/5), leading to Perthes-like and osteoarthritic changes and severe hip pain in the early thirties (2/2 adults, having reached this age). The marked retardation of carpal bone age may lead to unnecessary clinical evaluation for endocrine disorders. Less frequent clinical manifestations of ASPED are hyperextensibility of the interphalangeal joints (7/9) and hypodontia (4/7). Other types of ASPs are observed in brachyphalangy type C, spondylo-megepiphyseal-metaphyseal dysplasia, and other conditions. The concept of mild bone abnormalities as specific markers for genetic disease, as with cone-shaped epiphyses and now evident in ASPED, may also be useful for ASPs in general.

Pediatric pelvis: radiographic appearance in various congenital disorders.

This article presents the spectrum of pelvic abnormalities in developmental diseases of bone. The pelvis comprises the ilium, ischium and pubis, and the sacrum. Knowledge of pelvic embryology and normal development is essential in recognizing pelvic abnormalities and disorders, which involve the number of bone elements, rate of ossification, density, and size or shape. Anarchic development of bone and dysplasias identifiable at birth must also be considered. The pelvis is important in the evaluation of such disorders because of the frequent, varied, and often specific radiologic abnormalities. The pelvis may also be the first evidence for a congenital malformation syndrome because it is often included in routine radiographic examinations.

Variation of quantitative and qualitative changes of enchondral ossification in heterozygous achondroplasia.

Whereas the radiologic features of achondroplasia--the most common type of skeletal dysplasia in adults--are clearly defined there is still some debate about the severity and the type of histologic changes. Earlier descriptions reported severe disturbance of enchondral ossification to be typical of achondroplasia: They are, however, misleading by dealing mostly with cases of lethal neonatal dwarfism (e.g. thanatophoric dysplasia). Newer findings confirmed that only minor, quantitative lesions are typical of heterozygous achondroplasia. But even in recent years some observers noted more severe changes of enchondral ossification. An extensive histologic skeletal survey in a newborn achondroplastic male revealed remarkable findings: It clearly showed that in addition to a generalized, but moderate narrowing of the zones of enchondral ossification focal severe changes were present in various epiphyseal plates including clusterlike arrangement of enlarged chondrocytes, vacuolization, premature calcification and important fibrosis of cartilagineous matrix with membranous ossification. Our findings thus enable us to reconcile the seemingly divergent statements made before.

Unknown syndrome: ischiadic hypoplasia, renal dysfunction, immunodeficiency, and a pattern of minor congenital anomalies.

We report a 6 year old male with a pattern of malformations and anomalies including intrauterine growth retardation, microcephaly, psychomotor retardation, a pattern of craniofacial anomalies (flat face, hypertelorism, epicanthic folds, strabismus, short nose, low set ears), hypospadias and cryptorchidism, bilateral partial cutaneous syndactyly between fingers 2 to 5 and toes 2 to 4, postaxial polydactyly of the fingers and toes, severe conductive hearing loss, hypoplasia of the ischiadic bones, complex renal dysfunction, hypogammaglobulinaemia with proneness to bacterial infections of the upper and lower respiratory tract, and recurrent pseudomembranous enterocolitis. The parents are cousins of Turkish origin.