Severely delayed epiphyseal ossification dysplasia with normal stature
Abstract
We report on a pair of dizygotic twins born to consanguineous parents, showing an extreme delay in skeletal maturation (roughly corresponding to the time of birth at the age of 4 10/12 years), mild metaphyseal irregularities, and normal to large stature (+ 1 to + 2 SD) with normal growth pattern, long fingers, generalized small joint hyperlaxity with flat feet, genua valga, and low normal intellectual development. This disorder was not associated with abnormal endocrine function or abnormal Ca/P metabolism. This epiphyseal disorder is compatible with autosomal recessive inheritance.© 2003 Wiley-Liss, Inc.
INTRODUCTION
Epiphyseal dysplasias (ED) are a heterogeneous group of disorders characterized by misshaped epiphyses of long bones, with or without vertebrate and/or metaphyseal anomalies. Short stature and, less often, brachydactyly are common findings in ED, and the pattern of bone maturation is variably delayed. We report here on two sibs with a unique combination of anomalies consisting in extreme delay in epiphyseal bone ossification associated with tall stature and long fingers, a condition that could be recessively inherited.
FAMILY REPORT
The two patients reported here were the product of a spontaneous twin pregnancy. Dizygotic twinning was demonstrated by microsatellite analysis (not shown). The Tunisian parents were first cousins. The father, aged 42 years, at the time of birth was 182 cm tall (+ 1.5 SD). He had had mild, non-progressive scoliosis that did not require any treatment. The mother, age 25 years, was 160 cm tall (mean). Both were in good health and had no other relevant medical history. Familial history was not contributory.
Patient 1
This boy was born at 36 weeks of gestation, by cesarean section. B.W. was 2,790 g (50–75th centile), B.L. was 47 cm (50th centile) and OFC 33.5 cm (50–75th centile). Bilateral ulnar deviation of the fingers was noted neonatally. Skeletal survey at the age of 2 years showed a major delay of ossification of ischiopubic rami, absence of ossification of the calcaneum and the other epiphyseal nuclei that are usually present at this age, brachymesophalangy V, and normal ossification of skull and clavicles. His bone maturation was considered at the level of a newborn infant. Somatic growth was characterized by a shift from the mean to + 2 SD between 6 months and 2 years, and by regular growth following the + 2 SD curve since that time. Psychomotor development was normal. Obesity progressed from + 2 SD at the age of 3 years to his present state, and was attributed to poor dietary habits without compulsory hyperphagia. Since the age of 3 years, he complained of diffuse pain in the lower limbs and large joints and the parents noted easy fatigability.
At the last evaluation, at the age of 4 10/12 years, he was 117 cm tall (+ 2.5 SD), had an arm span of 118 cm and a pubic-ground height of 54 cm, weighted 25 kg (+ 4 SD); and had an OFC of 52 cm (+ 0.5 SD). Face was normal (Fig. 1a). Spine was not deviated. Ulnar deviation of the fingers was not present anymore. Hands were narrow but of normal length (14.5 cm, > 97th centile) with long palms (7.5 cm, > 97th centile), long fingers with squared tips (Fig. 1c), and clinodactyly V. He had flat feet. There was clear generalized joint hyperlaxity, most prominent in the hands and elbows, with mild genua valga. Skin was normal. Neurological assessment was unremarkable, but the child was obviously clumsy, with difficulties in coordination but normal intelligence and unremarkable school achievement. Radiological survey (Fig. 2) disclosed an impressive, persisting delay of bone maturation. On radiographs performed at the age of 4 10/12 years, the following anomalies were noted:
Clinical appearance of patients. Frontal view of patient 1 (a) and patient 2 (b). Close up of the hands of patient 1 (c) and patient 2 (d) illustrating long fingers with square tips.
Patient 1, age 5 years. a: Narrow-shaped pelvis, hypoplastic femoral heads, and enlarged upper femoral metaphyses. b: Knee showing small epiphyses. c: Ankle joint showing abnormal medial placement of the hypoplastic lower tibial epiphysis.
General appearance
Normal shape and bone density of skull, ribs, clavicles and vertebrae, except for somewhat tall and squared lumbar vertebrae on profile view. Normally shaped diaphyses with normal cortical thickness. Mild metaphyseal irregularities and flaring, more obvious on upper femoral (Fig. 2a) and lower tibial metaphyses.
Hands
Marked ossification delay: no epiphyseal nuclei except 2 pseudoepiphyses on 2nd and 3rd metacarpals; brachymesophalangy V; mild irregularity of the modeling of the phalangeal shaft with medullary stenosis; apparent “hypertrophy” of the cartilages at the metacarpophalangeal joint (Fig. 2b).
Feet
Similar pattern with ossification of talus, calcaneus and cuboid bones, and absence of ossification of smaller tarsal bones and metatarsal epiphyses.
Pelvis
Narrow iliac wings; marked delay of ossification of iliopubic and, to a lesser degree, of ischiopubic rami; small, irregular, horizontal acetabular roofs, broad femoral necks with mild valgus, small, irregular femoral epiphyses.
Tibia
The ossification center of lower tibial epiphyses had an unusual medial location, close to the inner malleolus (Fig. 2c).
Several biological investigations were performed, with normal results. These included karyotype, thyroid function tests (T3, T4, TSH), phosphocalcic metabolism (calcemia, magnesemia, phosphatemia, calciuria and phosphaturia/24h, PTH, TCT, 1-25OH-D3), metabolic screening (plasma and urine amino acids, urine organic acids, ammonemia, fasting and postprandial lactate and pyruvate, VLCFA, pipecolic acid, plasmalogenes, phytanic acid, sialotransferrin electrophoresis), and serum enzymes (CPK, TGO, TGP, ãGT, LDH). EMG at the age of 3½ years was considered normal, as well as conduction velocities.
Patient 2
This boy was the twin of patient 1. B.W. was 2,080 g (10–25th centile), B.L. was 47.5 cm (50th centile) and OFC 34 cm (75th centile). He had normally shaped forearms. Skeletal survey at the age 2, 5 prompted by the anomalies observed in his brother, similarly showed a major delay of ossification. His bone maturation was like that of a newborn infant. Somatic growth was characterized by a regular growth between + 1 SD and + 2 curves. Psychomotor development was normal. Since the age of 3 years, he had the same complaints as his brother: diffuse pain in the limbs and easy fatigability.
At the last evaluation, at the age of 4 10/12 years, he was 110.5 cm tall (+ 1 SD), weighed 20 kg (+ 1 SD); and had an OFC of 53 cm (+ 1 SD). Face was normal (Fig. 1b). Spine was not deviated. Hands had the same slender appearance as those of his brother (Fig. 1d). He had flat feet, bilateral genua valga, and generalized joint hyperlaxity, most prominent in the hands and elbows. Skin was normal. Neurological assessment was normal, but the child was also clumsy, with difficulties in coordination. Psychomotor evaluation showed…
Radiological survey showed an ossification pattern almost identical to the one of his brother: the only difference being complete absence of ossification centers in the carpals and metacarpals (Fig. 3), and a lesser degree of ossification of femoral heads (Fig. 4).
Patient 1. Radiograph of the hand at the age of 5 years demonstrating extreme ossification delay of the carpal bones and epiphyses.
Patient 2, age 5 years. a: Pelvis with minimal ossification of femoral heads. b: Hand lacking all ossification centers.
DISCUSSION
Calcification of growing cartilage follows a remarkably regular pattern in humans, although mild variations in sequence exist between ethnic groups [Poznanski, 1984]. Disorders of ossification of the skeleton leading to apparently delayed bone age (either harmonious or disharmonious) can roughly be divided in five large groups [Kozlowski and Beighton, 2001]. The first one includes the primitive disorders of cartilage formation, as in a/hypochondrogenesis; the second one includes the disorders affecting osteogenesis, such as most types of epiphyseal, (epi)metaphyseal and spondylo(epi)metaphyseal dysplasias; atelosteogenesis, opsismodysplasia; the third group encompass disorders affecting bone modeling, such as Melnick-Needles osteodysplasia, ischiopatellar syndrome, cleidocranial dysostosis; the 4th group incorporates endocrine disorders such as GH deficiency, hypopituitarism, hypogonadism, insulin receptor deficiencies, and hypothyroidism; the last group is a set of multiple congenital anomalies syndromes, such as various chromosomal disorders, campomelic dwarfism, Seckel, Rubinstein-Taybi, CODAS, or Eiken syndromes [Canepa et al., 1999; Hall and Washburn, 2000].
In most cases of intrinsic bone disorders, abnormal epiphyseal ossification goes together with abnormal bone growth. This leads to a shortness of the bony parts that have abnormal ossification and thus to variable degree of limb shortness, affecting all or specific segments. In many cases, the children with delayed bone age will show short stature and short hands.
The family depicted here is unique because of its combination of extreme delay in bone mineralization associated with a normal to exaggerated growth pattern, leading to tall stature and long fingers. This aspect is not present in any other causes of delayed skeletal maturation, and permits easy exclusion. Even though the pathogenetic mechanism leading to such a delay in ossification is unknown, and histologic data are unavailable, the occurrence of this disorder in two sibs born to consanguineous parents is a reasonable argument for a genetic basis and recessive inheritance.
Acknowledgements
The authors thank Dr. P. Maroteaux and Dr. M. Le Merrer for their helpful comments about this family.
