medwireNews: A diagnosis of pseudohypoparathyroidism type IA (PHPIA) should be considered for infants who present with a combination of congenital hypothyroidism (CH), parathyroid hormone (PTH) resistance, early-onset obesity or minor dysmorphic features, Israeli clinicians suggest.
The team highlights that the clinical presentation of PHPIA and the Albright hereditary osteodystrophy phenotype is “highly variable” and emphasizes that “molecular analysis is recommended since the complete clinical phenotype may develop a long time after initial presentation.”
Hanna Ludar (Clalit Health Services, HaNevi’im) and co-workers report the long-term outcomes for a cohort of eight girls and one boy from six families who had a molecular diagnosis of PHPIA or inactivating PTH/PTH-related protein signalling disorder (iPPSD).
Five children had GNAS missense mutations, two had GNAS deletions and two frameshift mutations, with four of these alterations not previously documented, the researchers say in The Journal of Clinical Endocrinology & Metabolism.
While acknowledging the limitations of a small study population for confirming correlations between genotypes and phenotypes, they note that children with truncating mutations had a higher peak BMI than those with missense mutations (4.95 vs 3.36 standard deviation score [SDS]) and a taller final height (–1.37 vs –3.64 SDS).
The children were referred for care at an average age of 2.4 years because of CH (n=5), short stature (n=2) or obesity (n=2) and followed-up for a mean of 13.4 years. One patient died aged 1.3 years following cardiac surgery for congenital vascular ring repair.
Ludar et al report that all children had mild-to-severe developmental delay and brachydactyly, with shortened metacarpal bones noted in seven.
Seven patients had early-onset obesity at an average age of 2.05 years and BMI peaked on average at 5.0 years of age, at a mean SDS of 4.0, before falling to 1.9 SDS at an average 14.5 years of age. However, twin sisters failed to thrive in their early years before developing obesity at age 9.0 and 10.0 years, with BMI peaking during their second decade.
Three patients had elevated glycated haemoglobin levels, two of whom had impaired glucose tolerance at age 13 years that had resolved by age 20 years. One patient had severe insulin resistance requiring metformin at age 6 years, the researchers say. Patients also experienced mild hypertriglyceridemia, hypercholesterolemia and low high-density lipoprotein levels.
“This low rate of metabolic complications, despite severe obesity, may be attributed to the young age of our patients and the subsequent improvement in BMI after reaching an early peak”, remark the investigators.
At the time of referral, PTH serum levels were elevated in six patients. Although calcium levels were initially within the normal range in all patients, and remained so in three patients, hypocalcaemia was detected at an average of 5.9 years in six patients who were treated with calcium supplement and alfacalcidol.
“The absence of hypocalcemia or elevated PTH at an early age does not exclude the diagnosis of PHPIA, suggesting that long-term follow-up is necessary in order to make the clinical diagnosis”, write Ludar and co-authors.
Neonatal screening identified low total thyroxine levels in seven of eight screened patients and CH in five patients. Seven children began levothyroxine therapy between the ages of 1 and 8 months, one patient started treatment at 16.9 years and one patient maintained normal free thyroxine levels throughout follow-up.
Thyroid function at referral also showed elevated thyroid-stimulating hormone (TSH) with normal free thyroxine in all patients except one patient with “mildly low” levels.
Radionuclide screening was conducted in eight patients; five patients had a normal sized thyroid gland, one patient had a small gland with low uptake and two sisters had an atrophic thyroid.
“Our findings suggest that a diagnosis of CH with biochemical characteristics of TSH [resistance] in infancy should raise suspicion for the diagnosis of PHPIA, years prior to the appearance of the overt clinical phenotype, warranting long-term follow-up”, the researchers advise.
Overall, two of the nine patients had growth hormone deficiency (GHD), diagnosed at 8 years and 14 years; one patient was treated with GH therapy at age 14 years but did not experience an improvement in growth velocity.
Six girls went through puberty during follow-up with a “mildly delayed” onset at an average age of 11.5 years and menarche at an average 14.1 years of age. Two patients had “exaggerated” luteinising hormone and follicle-stimulating hormone levels on gonadotopin-releasing hormone stimulation and were diagnosed with polycystic ovary morphology. Two patients had primary amenorrhea and three patients had secondary amenorrhea.
Although all but two patients were of normal height during childhood, the girls had a pubertal growth spurt of just 5.7 cm and a total pubertal growth of 12.4 cm, attaining a final adult height of 146.3 cm and a height SDS of –2.5.
“It has recently been speculated that impaired melanocortin 4 receptor signaling, promoting accelerated growth, may counterbalance the negative effects of partial GHD on growth during early childhood, explaining the normal height observed until puberty in most of our patients”, conclude Ludar and co-workers.
By Lynda Williams
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