Short Fourth and Fifth Metacarpals FREE

A 9-year-old girl born of nonconsanguineous parents presents with a history of recurrent generalized tonic-clonic seizures since age 7 months, uncontrolled with 3 antiepileptic agents. The mother reports that the child has stunted growth and decreased cognitive function compared with other children her age. Physical examination is remarkable for short stature, round face, positive Chvostek sign, brachydactyly, and absence of outer 2 knuckles (fourth and fifth digits) on making a fist. Remainder of the physical examination results are unremarkable. Laboratory studies reveal total serum calcium level of 6.3 mg/dL (reference range, 8.7-10.2 mg/dL); serum phosphorous, 6.9 mg/dL (reference range, 2.5-4.3 mg/dL); alkaline phosphatase, 126 U/L (reference range, 33-96 U/L); and serum albumin, 4.2 g/dL (reference range, 3.5-5.5 g/dL). Twenty-four hour urinary calcium–creatinine ratio is 0.10. Thyroid-stimulating hormone is 65.18 mIU/L (reference range, 0.34-4.25 mIU/L), with a free thyroxine level of 0.54 μg/dL (reference range, 5.4-11.7 μg/dL). Concentrations of serum cortisol and insulinlike growth factor 1 are within reference range for the age and sex of the patient. Bilateral hand x-ray shows shortened fourth and fifth metacarpals (Figure).

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Pseudohypoparathyroidism

D. Order an intact parathyroid hormone measurement

The key clinical feature in this case is symptomatic hypocalcemia with short fourth and fifth metacarpals. The differential diagnosis for short fourth and fifth metacarpals includes traumatic or infectious causes, Turner syndrome, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, basal cell nevus syndrome, sickle cell disease, hereditary multiple exostosis, and homocystinuria. Only pseudohypoparathyroidism includes both hypocalcemia and short metacarpals. Therefore, measuring intact parathyroid hormone level will support the diagnosis of pseudohypoparathyroidism.

Pseudohypoparathyroidism is a group of inherited disorders characterized by symptomatic hypocalcemia and skeletal defects. Findings of low calcium and high phosphate levels are consistent with true hypoparathyroidism. However, elevated parathyroid hormone levels reflect hormone resistance, hence the name pseudohypoparathyroidism. There are 4 types of pseudohypoparathyroidism based on serum parathyroid hormone levels, urinary cyclic adenosine monophosphate (cAMP) response to exogenous parathyroid hormone, Albright hereditary phenotype (AHO), and Gs-α deficiency.¹ These are pseudohypoparathyroidism types Ia, Ib, II and pseudopseudohypoparathyroidism, respectively.

Pseudohypoparathyroidism type Ia differs from types Ib and II by the presence of AHO phenotype and Gs-α subunit deficiency. Urinary cAMP response to parathyroid hormone and increased serum parathyroid hormone levels are common to both pseudohypoparathyroidism types Ia and Ib. Pseudopseudohypoparathyroidism is characterized by the presence of AHO phenotype and Gs-α subunit deficiency with absence of other features of pseudohypoparathyroidism.

Pseudohypoparathyroidism type Ia is the most common. Classic features include the AHO phenotype (round face, short stature, brachydactyly),² as seen in this patient. Premature closing of the epiphysis results in short phalanges, typically of the fourth and fifth metacarpals. Absence of AHO phenotype and normal Gs-α subunit in fibroblasts in pseudohypoparathyroidism type Ib distinguishes it from type Ia. Common features to both type Ia and type Ib include elevated parathyroid hormone levels and reduced urinary cAMP levels to exogenous administration of parathyroid hormone.

Transmission of parathyroid hormone type Ia follows genetic imprinting that involves selective inactivation of a paternal or maternal allele by methylation of gene loci. The Gs-α subunit of the GNAS gene on chromosome 20 is paternally imprinted (silenced) in the renal cortex. Therefore, mutations in the maternal allele lead to loss of function in the kidney and result in expression of pseudohypoparathyroidism type Ia phenotype. Because there is selective resistance to parathyroid hormone in the proximal renal tubules (and not in the distal), urinary calcium excretion is not affected.³ Mutations in the paternal allele are not expressed in the kidney, do not affect renal tubular function, and therefore present with the phenotype of pseudopseudohypoparathyroidism.⁴

Other endocrine deficiencies due to resistance to target hormones are commonly seen in pseudohypoparathyroidism type Ia. Thyroid tissue, like renal cortex, demonstrates paternal imprinting; therefore, there is preferential expression of the maternal allele.⁵ The thyroid profile in this patient was consistent with primary hypothyroidism.

Vitamin D deficiency in children (rickets) is characterized by hypophosphatemia, bony abnormalities (genu varum, costochondral swelling), and radiological changes in metacarpals (spaying, fraying, and widening due to metaphyseal hyperplasia). A parathyroid scan is used to diagnose hyperparathyroidism and not hypoparathyrodism. Anticonvulsant drug therapy induces acquired vitamin D deficiency by increasing its peripheral conversion to inactive metabolites and/or causing resistance to its action. Cause of seizures in the patient described here was secondary to hypocalcemia that existed prior to initiation of anticonvulsant drug therapy.

Intact parathyroid hormone level was 147 pg/mL (reference range, 8-51 pg/mL). In the setting of hypocalcemia, elevated parathyroid hormone, and typical radiological findings, a diagnosis of pseudohypoparathyroidism was made. The patient was treated with low-dose calcium, calcitriol, and levothyroxine. The use of calcitriol rather than cholecalciferol was deliberate to counter the resistance of parathyroid hormone, imparing the conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol. The patient was encouraged to follow up biannually with measurement of serum calcium and creatinine levels, parathyroid hormone, thyroid-stimulating hormone, and 24-hour urinary calcium–creatinine ratio for titration of therapy.