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A 41-month-old female child was referred to the endocrine clinic for evaluation of poor growth, and delayed motor and mental milestones. She was the only child born out of a non-consanguineous marriage. There was no history of hypothyroidism or goitre in the parents. There was no family history of congenital hypothyroidism. Clinical evaluation revealed a lethargic child with dry skin, open anterior fontanelle, protuberant abdomen and short limbed dwarfism. Her bone age was less than 2 years and height age was 20 months. Her skull X-ray is shown in the figure.
- What is the diagnosis?
- What abnormalities are shown in the skull X-ray ?
- What other skeletal abnormalities are seen in this condition?
This patient has congenital hypothyroidism. Detailed clinical evaluation revealed, in addition to the above findings, an enlarged tongue, coarse facial features, generalised hypotonia, hoarse cry, and delayed relaxation of tendon jerks. There was no goitre. Serum thyroid-stimulating hormone levels were 51 mU/l (normal 0.5–5 mU/l), serum thyroxine levels were 10 nmol/l (64–154 nmol/l) and serum triiodothyronine (T3 levels were 0.2 nmol/l (1.1–2.9 nmol/l). Sodium [99mTc]pertechnetate scintiscanning revealed negligible uptake in thyroid region. This investigation profile is consistent with thyroid dysgenesis or agenesis leading to sporadic congenital hypothyroidism. Congenital hypothyroidism has an incidence of 1 in 3500–4000 and is easily picked up by neonatal screening. If diagnosed and treated at an early stage the manifestations of hypothyroidism can be reversed and/or prevented.
The skull X-ray displays intrasutural or wormian bones along lambdoid (broad arrow) and coronal sutures (narrow arrow). The anterior fontanelle is visualised (delayed closure of anterior fontanelle, arrow head). These are typical skull X-ray findings in congenital hypothyroidism.1 Wormian bones disappear when bone age reaches 5 years. These bones may also be seen in cleidocranial dysplasia, pyknodysostosis, acro-osteolysis (Hajdu-Cheney syndrome) and osteogenesis imperfecta.
In congenital primary hypothyroidism, the skull may be brachycephalic (a result of endochondral growth retardation at the base of skull). The sella is small and bowl shaped in young children and larger and rounded (cherry sella) in older children due to rebound hypertrophy of the pituitary gland. The paranasal sinuses are underdeveloped and facial bones are hypoplastic. An increased thickness of bones of the cranial vault with narrow diploic space may be seen. Development of teeth is delayed; primary teeth remain for several years beyond the normal time for exfoliation. Comparable delay occurs in appearance of permanent teeth. Unerupted teeth are structurally abnormal and are subject to caries. Dental defects tend to parallel the delay in ossification of the skeleton. The poorly developed jaw shows gross dental crowding.
Epiphyses are retarded in appearance and closure. When ossification or epiphyseal dysgenesis does occur, it is often from multiple sites within the epiphysis. This leads to a spotted or fragmented appearance on X-ray. This feature is most commonly seen in femoral and humeral heads, and in the navicular bone of the foot. Epiphyseal disturbances, particularly in the femoral head, persist beyond a bone age of 8 years. Femoral epiphyseal dysgenesis may resemble Perthe's disease, though Perthe's disease is usually unilateral. The incidence of slipped capital femoral epiphysis is increased in these cases of hypothyroidism.2 The long bones are short and this leads to disproportionate (short limbed) dwarfism. Dense transverse bands at metaphyseal ends may be present very early in life, but they tend to disappear by a bone age of 6 months. The pelvis is often narrow with coxa-vara deformity.
In severe involvement, bullet-shaped vertebrae are seen (usually T-12 or L-1). This is due to some degree of flattening of vertebral bodies with forward slipping of one vertebra over another, resulting in thoracolumbar gibbus. Disc spaces may be widened. Diffuse osteoporosis of vertebral bodies leads to the appearance of ‘picture framing’ of vertebral bodies. Increased density of the skeleton is seen in some cases.
The thyroid hormone is important for regulation of normal growth, development and maturation of tissue. In hypothyroidism pathological changes include a marked decrease in cartilage cell proliferation. The osseous tissue abuts the cartilage zone; this forms a barrier to longitudinal growth of the bone. Growth failure is due to both impaired protein synthesis and reduction in insulin-like growth factor-1 levels.3 The decrease in protein synthesis is reflected in retardation of skeletal and soft tissue growth. Thyroid hormone deficiency thus impairs secretion as well as effectiveness of growth hormone.
Bone and skeletal manifestations of hypothyroidism
delayed closure of fontanelle
relatively large sella
poorly developed paranasal sinuses
delayed dentition and dental caries
Epiphyseal centres of ossification
multicentric and irregular
delayed fusion and stippled appearance
epiphyseal dysgenesis (fragmented epiphyses)
flattening of vertebral bodies
increased width of intervertebral space
bullet-shaped vertebral bodies (usually L-1 and L-2)
dense transverse bands at metaphyseal ends
narrow with coxa-vara
Thyroid hormone effects on bone growth are direct and indirect. Proof of direct effect of thyroid hormones on bone growth needs to be demonstrated by thyroid receptors in bone cells and responses to thyroid hormones in vitro. Osteoclasts and osteoblasts have been shown to have a specificin-vitro response to T3. Little is known about the expression of thyroid receptor (TR) in developing bone and cartilage. In studies of osteosarcoma cells, expression of TR beta mRNA was greater than TR alpha mRNA in mature osteoblasts, whereas the opposite was true in fibroblast precursors of osteoblasts.4 This provides support for bone responsiveness to T3. Retinoid X receptor, a cofactor involved in the interaction of TR with T3-responsive element, has also been found to be expressed in osteoblasts.5
Thyroid hormone influences bone development and growth indirectly via growth hormone (GH) secretion and action. GH secretion and synthesis are stimulated in vivo by thyroid hormone. This effect is due to direct interaction of TR–T3 complex with GH gene regulating its expression. Thyroid hormone treatment has been reported to more than double the nocturnal GH values in hypothyroid children.6 Reversal of blunted GH response to GH-releasing hormone stimulation in hypothyroid children following treatment with thyroid hormone indicates a direct influence of thyroid hormone on GH secretion at the level of the pituitary rather than the hypothalamus.
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