New skeletal dysplasia with unique brachydactyly

We report on 2 male propositi, their mothers, and a maternal aunt with a new skeletal dysplasia associated with a unique pattern of digital malformation, variable mild short stature, and mild bowleg with proximal overgrowth of the fibula. The digital malformations comprise a pattern of brachydactyly which includes short, abducted thumbs, short index fingers, and markedly short, abducted great toes. The radiographic findings include hypoplastic thumbs and great toes with short first metacarpals and first metatarsals, absent distal phalanges of the index fingers and second toes, and coalescence of the carpal and tarsal bones. Radiographs of the long bones show mild metaphyseal and epiphyseal irregularity, tibial spurs, and relative elongation of the fibulae. The males are very similarly affected whereas the females show phenotypic variation and are generally less severely affected. The family histories from 2 fairly extensive pedigrees suggest X-linked dominant inheritance.     

Greenberg dysplasia (hydrops-ectopic calcification-moth-eaten skeletal dysplasia): prenatal ultrasound diagnosis and review of literature

A second pregnancy of young, nonconsanguineous parents of Macedonian ethnic origin was examined by ultrasound. Polyhydramnios and hydrops fetalis were found as well as severe short limb, short stature, and cystic hygroma of the neck. An artificial abortion was performed at the age of 23 weeks. The radiological features included moth-eaten severely shortened long bones and ectopic calcifications of long bones, vertebral column, ribs, pelvis, larynx, trachea. In addition, the fetus had large head with depressed nasal bridge, severe platyspondyly, and short barrel-shaped trunk. Light microscopy demonstrated lack of chondrocyte columns and disorganization of the cartilaginous architecture. This is the seventh reported case of this rare form of lethal skeletal dysplasia.     

Skeletal dysplasia with short,angulated femora (kyphomelic dysplasia)

We report on an infant with broad and severely angulated short femora as the most salient manifestation of a generalized skeletal dysplasia. Other findings include congenital bowing of other long bones, narrow thorax, platyspondyly, micrognathia, and skin dimples. A marked improvement of the bowing and of the irregular flare of the metaphyses was noted over a period of 6 mo. Congenital bowing of long bones can be an isolated finding or associated with other anomalies, so the purpose of reporting all cases is important for further nosologic and pathogenetic elucidation. Because of the severity of the femoral involvement, the condition has been called kyphomelic dysplasia. It may be an autosomal recessive trait. recessive trait.     

Spondyloepimetaphyseal dysplasia (SEMD) Shohat type

Recently a distinct spondyloepimetaphyseal dysplasia (SEMD) was reported in three members of a Jewish family. We present a 3.5-year-old Mexican boy with disproportionate short stature, peculiar face, short neck, small chest, abdominal distension, lumbar lordosis, short limbs, marked genuavara, and joint laxity. Roentgenologic findings include short long bones, wide and flared metaphyses with irregularities, delayed epiphyseal ossification, platyspondyly and morphological changes of vertebral bodies and fibular overgrowth. The striking resemblance of this patient to those previously reported confirms this form of SEMD as a distinct entity. Autosomal recessive inheritance is supported and the designation SEMD Shohat type is proposed. © 1994 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.     

Sib pair with previously unreported skeletal dysplasia

We report on a consanguineous Lebanese family in which a sister and brother had developmental delay, dysmorphic facial appearance, narrow chest, prominent abdomen, and short limbs. Neonatal radiographs disclosed a bell-shaped thorax, short ribs, some with a cupped end, severe platyspondyly, square iliac bones, horizontal acetabula with medial and lateral spurs, hypoplastic ischia, short long bones, slight widening of the distal femoral metaphyses, and absence of epiphyseal ossification of the knees. The girl died at age 9 months as a result of respiratory insufficiency. A clinical and radiological follow-up of the boy showed that the axial hypotonia, minor anomalies, and short stature were still present, whereas the bone abnormalities had improved. Differential diagnosis suggests that this is a new type of chondrodysplasia.     

Natural history of clinical features in two brothers with acromesomelic dysplasia related to PRKG2

Acromesomelic dysplasias (AMD) are a group of skeletal dysplasia characterized by shortening of the middle and distal segments of the limbs. Recently, biallelic PRKG2 variants have been reported to cause a new type of AMD. We detected biallelic novel variant (c.1635-1G > C) in PRKG2 in two brothers with mild to severe short stature, short limbs, cubitus varus, and brachydactyly. Radiological examination showed platyspondyly with anterior beaking of the vertebral bodies, stubby long bones with metaphyseal flaring and moderate brachydactyly with cone-shaped epiphyses of the middle and proximal phalanges. Upper limb proportions of the older brother were clinically classified as rhizomelic, however radiologic findings supported acromesomelia, along with the elbow limitation. Annual follow-ups of the older brother from the age of 5 to 20 years revealed progression of short stature with age but platyspondyly and anterior beaking became less conspicuous. The younger brother showed milder short stature and less conspicuous disproportion of the limbs than those of the older brother; however, platyspondyly and anterior beaking were more prominent on the radiographs obtained at the same age. In conclusion, this report provides new insights into the natural history of AMD type PRKG2 confirming the intrafamilial heterogeneity.     

Sleep duration and mortality – Does weekend sleep matter?

Previous studies have found a U‐shaped relationship between mortality and (weekday) sleep duration. We here address the association of both weekday and weekend sleep duration with overall mortality. A cohort of 43,880 subjects was followed for 13 years through record‐linkages. Cox proportional hazards regression models with attained age as time‐scale were fitted to estimate multivariable‐adjusted hazard ratios and 95% confidence intervals for mortality; stratified analyses on age (<65 years, ≥65 years) were conducted. Among individuals <65 years old, short sleep (≤5 hr) during weekends at baseline was associated with a 52% higher mortality rate (hazard ratios 1.52; 95% confidence intervals 1.15–2.02) compared with the reference group (7 hr), while no association was observed for long (≥9 hr) weekend sleep. When, instead, different combinations of weekday and weekend sleep durations were analysed, we observed a detrimental association with consistently sleeping ≤5 hr (hazard ratios 1.65; 95% confidence intervals 1.22–2.23) or ≥8 hr (hazard ratios 1.25; 95% confidence intervals 1.05–1.50), compared with consistently sleeping 6–7 hr per day (reference). The mortality rate among participants with short sleep during weekdays, but long sleep during weekends, did not differ from the rate of the reference group. Among individuals ≥65 years old, no association between weekend sleep or weekday/weekend sleep durations and mortality was observed. In conclusion, short, but not long, weekend sleep was associated with an increased mortality in subjects < 65 years. In the same age group, short sleep (or long sleep) on both weekdays and weekend showed increased mortality. Possibly, long weekend sleep may compensate for short weekday sleep.     

Extending the phenotype of lethal skeletal dysplasia type al Gazali

In this study, we describe the clinical and radiological phenotype of two patients with a rare skeletal dysplasia type al Gazali. The phenotype is characterized by brachycephaly, flat face, hypertelorism, low-set ears, hypertrichosis, hypoplastic thorax, as well as short extremities with brachydactyly. Further characteristics are severe fetal hydrops, radiologic signs of increased bone density and short, poorly modeled tubular bones with wide diaphysis and smooth, rounded metaphyses. Cortical bones as well as vertebral endplates are thick and the skull is sclerotic with prominent parietal bones and a large anterior fontanel. Our cases suggest that skeletal dysplasia type al Gazali is a lethal condition and provide further evidence that it is inherited in an autosomal recessive manner. Both morphological and radiological features of these patients are very similar, which together with the previous report may indicate the presence of a new clinical entity in the group of skeletal dysplasias with increased bone density and metaphyseal and diaphyseal involvement. Surprisingly, histological analysis of the bone tissue and the growth plate shows completely normal structure, which suggests that the skeletal dysplasia type al Gazali is a systemic disorder resulting in increased bone density and restricted growth of the skeleton.     

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.     

Kyphomelic dysplasia in two sib fetuses.

We present the in utero appearances and postmortem radiographic findings of two sib fetuses, a male and a female, with features suggestive of kyphomelic dysplasia. The fetuses had severe bowing of the long bones, short, flared ribs, platyspondyly, metaphyseal flaring, skin dimpling, with normal external genitalia and karyotypes and a normal pregnancy. They were born to a mother with features of brachydactyly type E. Prenatal ultrasonography of each case showed a normal amount of amniotic fluid, a normal brain, a normal biparietal diameter, symmetrical bowing and shortening of the long bones, and a narrow thorax. Our cases provide support for a familial mode of inheritance for both sexes in kyphomelic dysplasia. Prenatal ultrasound examination can be offered in subsequent pregnancies.     

A newly recognized skeletal dysplasia with rhizomelic limbs and retinitis pigmentosa

A girl with severe pre- and post-natal short stature, low-pitched voice, retinitis pigmentosa, photophobia, short neck, broad thorax, platyspondyly, rhizomelic shortening of the long bones, bilateral subluxation of the hips, advanced maturation of the epiphyses, and apparently normal intellectual development is described. The girl's parents are first cousins. Two subsequent pregnancies had ended in spontaneous abortion with polyhydramnios and severe growth retardation. To the best of our knowledge, this association had not been previously reported, and may be considered a newly recognized syndrome.     

Spondylometaphyseal dysplasia with cone-rod dystrophy

The co-occurrence of skeletal dysplasia and ophthalmologic abnormality is extremely rare. We report on a boy of a unique form of spondylometaphyseal dysplasia associated with cone-rod dystrophy. He presented with postnatal severe short stature, progressive lower limb deformity with rhizomelic shortening of the long bones, prominent joints with limited mobility in knees and elbows, mild thoracic scoliosis, and vision impairment due to cone dystrophy. Correction of deformity and simultaneous limb lengthening was performed in bilateral femora and tibiae without major complications. Skeletal manifestations in addition to comprehensive ophthalmologic examinations were described in this patient who had been followed from infancy to 16 years of age.     

Familial lethal skeletal dysplasia with cloverleaf skull and multiple anomalies of brain,eye, face and heart: a new autosomal recessive multiple congenital anomalies syndrome

We report on a 'new' lethal familial short-limb bone dysplasia associated with multiple anomalies in three sibs born to Arabic-Muslim consanguineous healthy parents. Clinical abnormalities included short limbs and short hands, cloverleaf skull, frontal bossing, wide anterior fontanel, hypertelorism, bilateral microphthalmia, cataract, low-set ears, narrow chest, ambiguous genitalia, cardiac ventricular septal defect (VSD) and agenesis of the corpus callosum. Radiological abnormalities included cloverleaf skull, hypoplastic clavicles and scapulae, thin, wavy cupped ribs, flat vertebral bodies with coronal clefting and several unossified vertebral pedicles and hypo-ossification of the pubic bone. The main changes noted in the long bones consisted of short-bowed long bones with abnormal metaphyses and unossified epiphyses. Chondro-osseous morphology documented degenerating chondrocytes with disorganization of the hypertrophied cartilage and short disorganized columns of hypertrophied areas. An autosomal recessive mode of inheritance seems most likely.     

The novel R211Q POP1 homozygous mutation causes different pathogenesis and skeletal changes from those of previously reported POP1‐associated anauxetic dysplasia

Processing of Precursor RNA 1 (POP1) is a core protein component shared by two essential closely related eukaryotic ribonucleoprotein complexes: RNase MRP (the mitochondrial RNA processing ribonuclease) and RNase P. Recently, five patients harboring mutations in POP1 have been reported with severe spondylo‐epi‐metaphyseal dysplasia and extremely short stature. We report a unique clinical phenotype resulting from the novel homozygous R211Q POP1 mutation in three patients from one family, presenting with severe short stature but only subtle skeletal dysplastic changes that are merely metaphyseal. The RNA moiety of the RNase‐MRP complex quantified in RNA extracted from peripheral lymphocytes was dramatically reduced in affected patients indicating instability of the enzymatic complex. However, pre5.8s rRNA, a substrate of RNase‐MRP complex, was not accumulated in patients' RNA unlike in the previously reported POP1 mutations; this may explain the uniquely mild phenotype in our cases, and questions the assumption that alteration in ribosomal biogenesis is the pathophysiological basis for skeletal disorders caused by POP1 mutations. Finally, POP1 mutations should be considered in familial cases with severe short stature even when skeletal dysplasia is not strongly evident.     

“Baby rattle” pelvis dysplasia

We report an apparently previously undescribed lethal skeletal dysplasia, clinically resembling achondrogenesis, but with distinct radiologic and chondro‐osseous morphologic features. These comprise bifid distal ends of the long bones of the limbs, absent vertebral body ossification, a unique “baby rattle” pelvic configuration with tall and broad ilia, absent endochondral ossification, regions of mesenchymal cells within the resting cartilage, and abnormal mesenchymal ossification. © 2001 Wiley‐Liss, Inc.     

Phenotypic and molecular characterization of a novel case of dyssegmental dysplasia,Silverman-Handmaker type

Dyssegmental dysplasia, Silverman-Handmaker type (DDSH; #MIM 224410) is an autosomal recessive form of lethal dwarfism characterized by a defect in segmentation and fusion of vertebral bodies components (“anisospondyly”) and by severe limb shortening. It is caused by mutations in the perlecan gene (HSPG2), but so far, only three molecularly confirmed cases have been reported. We report a novel case of DDSH in a fetus that presented at 15 weeks gestation with encephalocele, severe micromelic dwarfism and narrow thorax. After termination of pregnancy, radiographs showed short ribs, short and bent long bones and anisospondyly of two vertebral bodies. The fetus was homozygous for a previously undescribed null mutation in HSPG2.     

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.