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.     

Radiologic changes in infancy in McKusick cartilage hair hypoplasia.

Cartilage hair hypoplasia (CHH), or metaphyseal dysplasia McKusick type, classically comprises short stature and scant fine hair. In this skeletal dysplasia there is a high incidence of immune deficiency and Hirschsprung disease, as well as a higher rate of malignancy. Clinical findings may be subtle in young children, and radiographic changes may be elusive. We present four children below age 2 in whom the clinical diagnosis of CHH was confirmed radiographically. We emphasize radiologically and clinically discernable anterior angulation of the entire sternum, a sign not previously described in this dysplasia.     

Association of kyphomelic dysplasia with severe combined immunodeficiency

Kyphomelic dysplasia is a distinct, rare, skeletal dysplasia with short angulated femora, bowing of long bones, short ribs, narrow thorax, and metaphyseal abnormalities. While immune deficiency occurs in other short stature/short-limb skeletal dysplasias and cartilage-hair hypoplasia, it has not been described with kyphomelic dysplasia. We report on an infant with this disorder who had profound humoral and cellular immunologic abnormalities consistent with severe combined immune deficiency (SCID). The infant died at age 2 months of overwhelming cytomegalovirus pneumonia. Kyphomelic dysplasia, as with other short stature/short-limb skeletal dysplasias, can be associated with immune deficiency and immune function should be investigated when this disorder is identified. © 1995 Wiley-Liss, Inc.     

RMRP mutations in Japanese patients with cartilage-hair hypoplasia

We examined 12 Japanese patients with metaphyseal chondrodysplasia (MCD) for mutations in the ribonuclease mitochondrial RNA processing gene (RMRP), and identified four novel mutations in two patients with typical and atypical cartilage-hair hypoplasia (CHH), a form of MCD characterized by extra-skeletal manifestations including hypoplastic hair and defective immunity. A patient with typical CHH had a 17-bp duplication at +3 and a de novo 182G > A. The other patient with atypical CHH had a 17-bp insertion at -20 and a 218A > G. Expression analysis revealed that the allele with this insertion mutation in the promoter region silenced the gene. Spectrum analysis of the mutations and polymorphisms in RMRP showed marked difference between the Japanese and other ethnic groups. Such ethnic and phenotypic difference should be taken into account in mutation analysis of the gene.     

Radiologic changes in infancy in McKusick cartilage hair hypoplasia

Cartilage hair hypoplasia (CHH), or metaphyseal dysplasia McKusick type, classically comprises short stature and scant fine hair. In this skeletal dysplasia there is a high incidence of immune deficiency and Hirschsprung disease, as well as a higher rate of malignancy. Clinical findings may be subtle in young children, and radiographic changes may be elusive. We present four children below age 2 in whom the clinical diagnosis of CHH was confirmed radiographically. We emphasize radiologically and clinically discernable anterior angulation of the entire sternum, a sign not previously described in this dysplasia. Am. J. Med. Genet. 86:312–315, 1999. © 1999 Wiley-Liss, Inc.     

Distinctive metaphyseal chondrodysplasia simulating cartilage hair hypoplasia

We report on a 5(1/2) year-old Italian girl with a distinctive form of metaphyseal chondrodysplasia simulating cartilage hair hypoplasia. The pattern of metaphyseal changes and the associated bony abnormalities differentiate this patient from all the recognized forms of metaphyseal chondrodysplasia.     

Pulmonary Follow-Up Imaging in Cartilage-Hair Hypoplasia: a Prospective Cohort Study

Cartilage-hair hypoplasia is a syndromic immunodeficiency with short stature, chondrodysplasia, and variable degree of immune dysfunction. Patients with cartilage-hair hypoplasia are prone to recurrent respiratory tract infections, and the prevalence of bronchiectasis ranges from 29 to 52%. Pulmonary complications contribute significantly to the mortality; therefore, regular lung imaging is essential. However, the optimal schedule for repeated lung imaging remains unestablished. We determined the rate and correlates of progression of structural lung changes in a prospectively followed cohort of 16 patients with cartilage-hair hypoplasia. We analyzed clinical, laboratory, and pulmonary functional testing data and performed lung magnetic resonance imaging at a median interval of 6.8 years since previous imaging. Imaging findings remained identical or improved due to disappearance of inflammatory changes in all evaluated patients. Patients with subtle signs of bronchiectasis on imaging tended to have low immunoglobulin M levels, as well as suffered from pneumonia during the follow-up. In conclusion, our results suggest slow if any development of bronchiectasis in selected subjects with cartilage-hair hypoplasia.

     

An unusual case of metaphyseal chondrodysplasia with an abnormal perilacunar matrix associated with agranulocytosis and hypoplasia of the thymus

Summary We report herein an unusual skeletal dysplasia in a 6-month-old boy characterized by metaphyseal dysplasia associated with agranulocytosis and hypoplasia of the thymus. A radiological survey revealed generalized metaphyseal abnormalities showing widening and increased density. Pathological changes in the chondro-osseous tissues were unusual and distinctive. There was widespread evidence of abnormal chondrocytes with an abnormal perilacunar matrix containing a PAS-positive, diastase resistant substance. Chondrocyte maturation and regular columnar arrangement were absent in most growth plates with only scattered ball-like nests of chondrocytes showing incomplete maturation. This case is a newly described form of osteochondrodysplasia.     

Biophysical and biochemical studies of the hair in cartilage-hair hypoplasia

The hair from four patients with classical cartilage-hair hypoplasia (CHH) was studied with respect to its stress-strain characteristics, amino acid composition, solubility in 6 M urea containing reducing agents, and the electrophoresis of the isolated S-carboxymethylated proteins in acrylamide gels containing 6 M urea. Many CHH hairs had the mechanical properties of hairs with reduced disulfide bonds and these properties returned to normal after five minutes' oxidation with 3 % hydrogen peroxide, There was decreased solubility of CHH hair with a deficiency of the filamenlous proteins when 0.1 M mercaptocthanol was the reducing agent; with 0.1 M dithiothreitol as reducing agent, the yield of proteins increased and the electrophoretic pattern was normal. The filamentous and matrix proteins of CHH hair have no gross structural defects, and it is suggested that the decreased reactivity of some disulfide bonds may he responsible for the abnormal biophysical and biochemical characteristics of this hair.     

Simplified gyral pattern with cerebellar hypoplasia in Sedaghatian type spondylometaphyseal dysplasia: a clinical report and review of the literature

We report on a patient with Sedaghatian type spondylometaphyseal dysplasia (SSMD) who presented with metaphyseal dysplasia, congenital atrioventricular block, simplified gyral pattern, hypogenesis of corpus callosum, and severe cerebellar hypoplasia. We want to emphasize that in this rare congenital lethal skeletal dysplasia with unknown etiology, central nervous system malformations might be a major component of the disorder and should be evaluated in detail to possibly uncover the underlying pathophysiology.     

Craniotubular dysplasia with severe postnatal growth retardation,mental retardation,ectodermal dysplasia,and loose skin: Lenz-Majewski-Like syndrome

The heterogeneous group of craniotubular dysplasias is characterized by modeling errors of the craniofacial and tubular bones. Some conditions in this category cause not only skeletal abnormalities but also a variety of mesoectodermal dysplasias, as exemplified in Lenz-Majewski syndrome (MIM 151050), which comprises craniodiaphyseal dysplasia, failure to thrive, mental retardation, proximal symphalangism, enamel hypoplasia, and loose skin. We report on a boy with a hitherto unknown multisystem disorder, including skeletal changes that were regarded as a form of craniotubular dysplasia. The patient had a large head, exophthalmos, a broad nasal root, anteverted nostrils, large auricles, thick lips, micrognathia, severe postnatal growth retardation with emaciation, severe mental retardation, sparse hair growth, enamel hypoplasia, and thin, loose skin with hyperlaxity. Skeletal changes consisted of thickened calvaria, sclerosis of the skull base and facial bones, thick ribs, and metaphyseal undermodeling of the tubular bones. In addition, generalized osteopenia was evident. The present disorder overlaps phenotypically with Lenz-Majewski syndrome; nevertheless, the absence of diaphyseal hyperostosis and proximal symphalangism in the present patient was not consistent with Lenz-Majewski syndrome. Am. J. Med. Genet. 71:87–92, 1997. © 1997 Wiley-Liss, Inc.     

New form of spondyloepimetaphyseal dysplasia (SEMD) in Jewish family of Iraqi Origin

We report a distinct type of spondyloepimetaphyseal dysplasia seen in 2 sibs and their second cousin, characterized by early onset severe short stature, small chest, and distended abdomen. They had short neck, severe lumbar lordosis, and marked genu varum due to fibular overgrowth and joint laxity. Radiographically, the patients had platyspondyly, initially noted during the first years of life, with central hypoplasia of the vertebral bodies. At a later age, the vertebrae appear squared with mild interpedicular narrowing. The long bone changes, which at early age resemble those seen in achondroplasia, later include general metaphyseal irregularities and significant epiphyseal ossification delay. These patients present a previously undescribed form of spondyloepimetaphyseal dysplasia, most probably transmitted as an autosomal recessive tract. © 1993 Wiley-Liss, Inc.     

Variable expression in ankyloblepharon-ectodermal defects-cleft lip and palate syndrome

The ankyloblepharon-ectodermal defects-cleft lip and palate (Hay-Wells) syndrome is a rare autosomal dominant form of congenital ectodermal dysplasia. It is characterized by coarse, wiry, sparse hair; dystrophic nails; slight hypohidrosis; scalp infections; ankyloblepharon filiforme adnatum; hypodontia; maxillary hypoplasia; and cleft lip and palate. To date, 12 patients have been reported; however, the diagnosis has been questioned in 3 of these patients. We report 2 additional patients, one of whom has nasal speech but not cleft palate, in contrast to all other reported patients. This entity must be distinguished from numerous other forms of ectodermal dysplasia, especially those forms that can be associated with oral clefts and/or ankyloblepharon.     

Variable expression in ankyloblepharon–ectodermal defects–cleft lip and palate syndrome

The ankyloblepharon-ectodermal defects-cleft lip and palate (Hay-Wells) syndrome is a rare autosomal dominant form of congenital ectodermal dysplasia. It is characterized by coarse, wiry, sparse hair; dystrophic nails; slight hypohidrosis; scalp infections; ankyloblepharon filiforme adnatum; hypodontia; maxillary hypoplasia; and cleft lip and palate. To date, 12 patients have been reported; however, the diagnosis has been questioned in 3 of these patients. We report 2 additional patients, one of whom has nasal speech but not cleft palate, in contrast to all other reported patients. This entity must be distinguished from numerous other forms of ectodermal dysplasia, especially those forms that can be associated with oral clefts and/or ankyloblepharon.     

Radiological evolution in IMAGe association: a case report

IMAGe association is a recently recognized multi-system disorder of unknown etiology. IMAGe is a mnemonic acronym that stands for Intrauterine growth retardation, Metaphyseal dysplasia, Adrenal hypoplasia congenita, and Genital anomalies (OMIM 300290). Suspicion for the disorder is readily raised by the distinctive clinical and endocrinological constellation, and radiological identification of metaphyseal dysplasia is crucial for the diagnosis. However, knowledge of the onset, evolution, severity, and variation of the metaphyseal dysplasia is currently limited. We illustrate the radiological evolution of an affected girl from her premature birth to early childhood. Her initial skeletal changes included thin ribs, delayed ossification of the juxtatruncal bones, and delayed epiphyseal ossification. The former two became less conspicuous during infancy. Metaphyseal dysplasia was not discerned at birth. However, mild metaphyseal cupping, sclerosis and longitudinal striations became manifest in late infancy, and then progressed with age. It is thought that the skeletal alterations in IMAGe association encompass retarded endochondral ossification normalized later on and mild metaphyseal dysplasia of postnatal onset.     

Cephalometric analysis of Rapp-Hodgkin syndrome.

Rapp-Hodgkin syndrome (RHS) is a rare form of ectodermal dysplasia with variable involvement of the hair, eyes, sweat glands, nails, and teeth. Oral findings may include hypodontia, hypoplastic enamel, cleft lip/palate, and a pronounced midfacial hypoplasia. The objective of this study was to determine if the pronounced midfacial hypoplasia is the result of a true tissue hypoplasia or displacement of midfacial tissues. We have identified a family in which three members, a mother and two daughters, display clinical features characteristic of RHS. Clinical and intraoral examination of these affected persons showed manifestations characteristic of RHS, and several new findings were observed, including subcutaneous abscesses, palmoplantar keratosis, and keratotic lesions located on the chest and trunk. To assess the midfacial hypoplasia, lateral cephalometric analysis was performed on lateral headplates. Results of the cephalometric analysis suggest that the midfacial hypoplasia results from both a deficiency and a displacement of the maxilla. These findings are significant because successful dental treatment of RHS relies upon accurate assessment of current and projected orofacial development, particularly for the skeletal relations of the maxilla and mandible.     

Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly

We report the familial occurrence in a French Canadian family of metaphyseal dysplasia associated to short stature and previously undescribed facial and acral anomalies. Facial manifestations include beaked nose, short philtrum, thin lips, maxillary hypoplasia, and dystrophic yellowish teeth. Acral changes include bilateral shortness of metacarpal 5 and/or 2nd middle phalanx of fingers 2 and 5. Dermatoglyphics show low TRC, distal or absent axial triradius, absent triradius C, and radial loop on digit 4. The syndrome appears to be an autosomal dominant trait.     

SPONASTRIME dysplasia: report of an 11-year-old boy and review of the literature

SPONASTRIME (SPOndylar and NAsal changes, with STRIations of the MEtaphyses) dysplasia is a rare, autosomal recessive bone disorder first described by Fanconi et al. [1983: Helv Paediatr Acta 38:267-280]. Radiographic findings include abnormal vertebral bodies with age-dependent changes, and striations of the metaphyses, scoliosis, and retarded ossification of the carpal bones. Physical features include severe short stature, lumbar lordosis, midface hypoplasia, frontal bossing, and a depressed nasal root. To date, 12 patients from 6 families have been reported. Four additional patients have been reported with a variant of this condition, which includes mental retardation. We report on an 11-year-old boy with features consistent with SPONASTRIME dysplasia. Height was 106.1 cm (-6 SD). He had a coarse appearing face with a depressed nasal bridge, short, upturned nose, and midface hypoplasia. Intelligence was normal. A clinical evaluation at 6 years of age suggested the diagnosis of spondyloepiphyseal dysplasia (SED). However, genetics evaluation at 11 years of age with repeat radiologic studies revealed delayed carpal ossification (-4 to -5 SD), metaphyseal irregularities and striations most notably in the distal femurs and the proximal tibias, lumbar lordosis, narrow interpedicular distances of the lumbar spine, and pear-shaped vertebral bodies. These findings were most consistent with the diagnosis of SPONASTRIME dysplasia, and not SED. Although radiographic findings of SPONASTRIME dysplasia are distinguishable from SED, the physical appearance may be similar. Many bone dysplasias have overlapping radiographic findings and clinical presentation but with different recurrence risks, making genetic counseling a challenge.     

COL2A1-related skeletal dysplasias with predominant metaphyseal involvement

Skeletal dysplasias induced by mutations in the collagen 2 gene (the so-called "type 2 collagenopathies") form a wide spectrum in severity and are distinguished by subtle clinical and radiographic differential signs. The unifying features are predominant involvement of the vertebral bodies and the epiphyses of the long bones ("spondylo-epiphyseal" pattern). A mild degree of metaphyseal dysplasia can be seen in the so-called Strudwick variant of spondyloepimetaphyseal dysplasia and is generally mild or absent in other forms.We report here on four individuals with COL2A1 mutations associated with marked metaphyseal involvement with only mild epiphyseal and spondylar changes. One patient who carried a Gly283Arg substitution had a pattern of metaphyseal dysplasia that corresponded precisely to what was termed "Murdoch type metaphyseal dysplasia" in 1960s and was renamed Strudwick type SEMD in 1980s; the second patient carried a Gly181Arg substitution and had severe metaphyseal dysplasia with fractures at the metaphyses reminiscent of the "corner fractures" or Sutcliffe type spondylometaphyseal dysplasia. The third patient also had major metaphyseal involvement but more epiphyseal changes than the others in this study and had a Gly922Arg mutation in COL2A1. The final patient had a small in-frame deletion and unusually ballooned and distorted metaphyses.While it remains true that most individuals with COL2A1 mutations have chondrodysplasia with a spondylo-epiphyseal pattern, metaphyseal involvement is not incompatible with a COL2A1 dysplasia and mutation analysis can be indicated. The observation of these individuals with metaphyseal dysplasia indicates that the phenotypic spectrum associated with mutations in type 2 collagen, the main cartilage protein, is even wider than hitherto assumed.     

Cartilage-hair hypoplasia in Finland: epidemiological and genetic aspects of 107 patients.

Cartilage-hair hypoplasia (CHH) is an autosomal recessive form of metaphyseal chondrodysplasia characterised by short limbed short stature, hypoplastic hair growth, and impaired cell mediated immunity and erythrocyte production. The syndrome is exceptionally prevalent among the Finns and among the Old Order Amish in the United States; sporadic cases have been reported from other countries. An epidemiological and genetic study of CHH in Finland showed 107 patients, 46 males and 61 females, in 85 families. Eighteen of them had died, seven before the age of 1 year. The living patients ranged in age from 1 to 51 years, median 21 years. The incidence was estimated to be 1:23,000 live births. Consanguinity was found in two families and interfamilial relationships in 20 families. Geographical distribution of the birth places of the patients and their great grandparents showed accumulation in a small area in western Finland and regional clusters were seen in other parts of the country as well. The result of the segregation analysis was in accordance with recessive inheritance with reduced penetrance.