Abstract
Summary
Short stature is a common complaint among pediatric visits and the differential diagnosis is extensive. Although some variations in growth are normal, deviation from normal growth is often the first symptom of chronic disease in children. This is true for hormone abnormalities including growth hormone deficiency, hypothyroidism and glucocorticoid excess. However, reduced growth velocity can also occur as the first sign of chronic anemia, malnutrition, deprivation (psychosocial dwarfism), chromosomal abnormalities, genetic syndromes and inflammatory bowel diseases. For the primary care provider, simple measures of standing height, sitting height, arm span, weight, body mass index (BMI) and bone age (BA) will lead to the correct diagnosis in most short children. Screening laboratory studies for endocrine disorders, a skeletal survey if skeletal disproportion is evident, a karyotype or microarray (microarray favored if developmental delay is also present) and genetic testing for monogenic disorders will lead to a specific diagnosis in an additional subset of short children. This case presented a diagnostic dilemma that spanned all these possibilities and served as a focal point for the review of normal growth and growth abnormalities.
Learning points
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Variations in growth can be normal variants (constitutional delay of growth and puberty or familial short stature) but deviation from normal growth can also be the first sign of an underlying pathological process.
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Measures of standing height, sitting height, arm span, weight, body mass index (BMI) and bone age (BA) will lead to the correct diagnosis in 50–80% of short children.
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Screening laboratory studies for endocrine disorders, a skeletal survey if skeletal disproportion is evident, a karyotype or microarray (microarray is favored if developmental delay is also present) and genetic testing will lead to a specific diagnosis in another 35% of short children.
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Pseudohypoparathyroidism (PHP) type 1A is due to a mutation in the alpha subunit of the stimulatory G protein of the guanine nucleotide-binding protein gene. Multiple hormone resistance often affects thyroid-stimulating hormone and, when presenting in the newborn period, can be misdiagnosed as common forms of congenital hypothyroidism.
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Molecular testing is an important component of confirming the diagnosis and PHP subtype, which can help guide management.
Introduction
Short stature is a common pediatric complaint. Some variations in growth are normal, but deviation from normal growth is often the first symptom of endocrine disorders that require treatment.
For the primary care provider, simple measures of standing height, sitting height, arm span, weight, body mass index (BMI) and bone age (BA) will lead to the correct diagnosis in 50-80% of short children (1). Screening laboratory studies for endocrine disorders, a skeletal survey if skeletal disproportion is evident, a karyotype or microarray (microarray favored if developmental delay is also present) and genetic testing for monogenic disorders will lead to a specific diagnosis in another 35% of short children (1).
Common variants of normal growth include constitutional delay of growth and puberty (CDGP) as well as familial (genetic) short stature (FSS). Both disorders are characterized by a gradual decline in growth velocity that begins around 18 months of age and then normalizes until puberty. Children with CDGP typically have family member(s) with a similar growth pattern and delays in bone age, pubertal onset, peak height velocity and final adult height. In contrast, children with FSS typically have family member(s) with short stature but no delays in bone age or the timing or tempo of puberty.
Caution should be taken in making these diagnoses as hormone deficiencies can mimic CDGP and dominantly transmitted forms of growth hormone deficiency or skeletal dysplasia can mimic FSS. For these reasons, screening laboratory studies should be performed to exclude pathology and typically include complete blood count, comprehensive metabolic profile, thyroid function tests, insulin-like growth factor-1 (IGF-1) and IGF-1 binding protein-3 (IGFBP-3). A dedicated skeletal survey is indicated for those with disproportionate growth. Features that suggest pathologic short stature (2) are summarized in Table 1.
Features that suggest pathologic short stature and warrant full evaluation (2).
Features suggestive of pathologic short stature |
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1. Severe short stature (height > 3 SD below the mean) |
2. Height > 1.5 SD below the mid-parental target height |
3. Height > 2 SD below the mean plus |
A. Height velocity over 1 year >1 SD below the mean for chronological age Or |
B. Decrease in height SD of >0.5 over 1 year in children >2 years of age |
4. In the absence of short stature |
A. Height velocity >2 SD below the mean over 1 year Or |
B. Height velocity >1.5 SD below the mean sustained over 2 years |
C. Signs indicative of an intracranial lesion |
D. Signs of multiple pituitary hormone deficiency |
E. Signs and symptoms of neonatal GHD |
a. Breech presentation |
b. Hypoglycemia |
c. Prolonged jaundice or direct hyperbilirubinemia |
d. Neonatal hepatitis |
e. Midline facial defects |
f. Micropenis (males) |
GHD, growth hormone deficiency; SD, standard deviation
Characteristic features in the present case, as in other conditions, can evolve over time and may not appear until late childhood or adolescence. This case demonstrates the difficulty of reaching a unifying diagnosis in some children with an evolving clinical picture.
Case presentation
An 11-year-old female was diagnosed with congenital hypothyroidism by initial newborn screening (initial thyroxine (T4) and thyroid-stimulating hormone (TSH) were reported as moderately elevated TSH). Confirmatory TSH (45.16 mU/L, reference range (RR): 0.70–5.70 mU/L), free T4 (fT4) (1.18 ng/dL, RR: 0.6–1.9 ng/dL) and total triiodothyronine (T3) (119 ng/dL, RR: 105–207 ng/dL) were obtained at 6 days of age, and she started levothyroxine replacement (25 μg daily) at 10 days of age when repeat TSH was elevated (24.04 mU/L) and fT4 was still normal (1.19 ng/dL). Despite adherence with therapy, she has persistent short stature. Her height is at the 1st percentile for age and sex despite a mid-parental target height of 165 cm (55th percentile). She has fallen behind in academic school performance and has had intermittent eye twitching for the past year. Due to concerns for short stature that was not congruent with the mid-parental target height, she presented to our team for evaluation at eleven years of age.
Physical examination
The patient was alert and cooperative. Her vital signs were within normal limits. Her height was 128.6 cm (1st percentile), weight was 42.3 kg (69th percentile), and BMI is 25.6 (96th percentile). Her face appeared round, and she had a stocky build. Additional pertinent findings included bilateral hearing loss, corrective lenses, a small firm thyroid without nodularity, disordered and delayed dental eruption, generally poor dentition with multiple caries, nontender subcutaneous nodules on her feet and left shin and normal muscle tone. Pubertal exam revealed no breast development and Tanner stage 2 pubic hair. Skeletal findings included brachydactyly with shortened metacarpals and phalanges. No muscular spasms were noted.
Investigation
The height of our patient was far below her mid-parental target height. Growth records document a gradually declining height velocity and body mass index (BMI) greater than the 95th percentile (Fig. 1). Because of that, she warranted full evaluation for pathological causes of short stature. Her skeletal findings suggested skeletal dysplasia, while the subcutaneous nodules and dental abnormalities suggested a disorder with calcium metabolism.
Growth charts. Height (A) and weight (B) curves for this patient. Limited growth records were available for review in her electronic health record but suggest a gradually declining height velocity between 7.5 and 11 years of age. Arrow indicates initial presentation to pediatric endocrinology.
Citation: Endocrinology, Diabetes & Metabolism Case Reports 2025, 1; 10.1530/EDM-24-0097
Her bone age (BA) radiograph showed an advanced skeletal age of 14 years (2.7 SD above chronological age) (3), diffuse osteopenia, and shortened metacarpals and phalanges, with the exception of the middle and proximal phalanx of the third finger (Fig. 2).
Bone age radiograph at age 11 years. The bone age is advanced to 14 years (2.7 SD above chronological age) according to comparison with the standards of Greulich and Pyle. Also noted are diffuse osteopenia, shortened metacarpals and phalanges with the exception of the middle and proximal phalanx of the third finger.
Citation: Endocrinology, Diabetes & Metabolism Case Reports 2025, 1; 10.1530/EDM-24-0097
Laboratory investigation revealed normal levels of TSH (2.4 mU/L, RR: 0.5–4.5 mU/L) and fT4 (1.48 ng/dL, RR: 0.8–1.8 ng/dL) while taking 112 μg levothyroxine daily. Her calcium (5.9 mg/dL, RR: 9.1–10.5 mg/dL) and ionized calcium levels (0.69 mmol/L, RR: 1.16–1.31 mmol/L) were critically low, and her phosphorus level was elevated (9.3 mg/dL, RR: 3.3–5.1 mg/dL). Her 25-hydroxy vitamin D level was normal (40.6 ng/mL, RR: 30.0–100.0 ng/mL). The intact parathyroid hormone (PTH) level was markedly elevated (630 pg/mL, RR: 10–65 pg/mL) and consistent with pseudohypoparathyroidism (PHP).
Treatment
The patient was admitted to the hospital where the electrocardiogram was normal. Intravenous calcium was given to correct severe hypocalcemia, and oral calcium and calcitriol were started. The urine calcium-to-creatinine ratio was appropriately low. Renal ultrasound showed no renal calculi or hydronephrosis. Levothyroxine was continued at 112 μg daily, her insulin-like growth factor-1 (IGF1) and IGF-binding protein-3 (IGFBP3) were normal, and gonadotropin levels were pubertal. A low-sodium diet and adequate hydration were recommended. Multiple carious teeth were repaired, and she was discharged from the hospital with plans to monitor her pubertal development.
Patient outcome and follow-up
The patient has continued a regimen of oral calcium, calcitriol and levothyroxine. Her serum calcium, fT4 and TSH levels remain normal. Her gonadotropin levels are in the pubertal range, and she is being closely monitored for pubertal progression.
Discussion
Final diagnosis
Genetic evaluation of our patient revealed a pathogenic mutation in the guanine nucleotide-binding protein (GNAS) at c.313-3_2. This mutation, along with the hypocalcemia, elevated PTH level, congenital hypothyroidism and skeletal abnormalities, confirmed the diagnosis of pseudohypoparathyroidism type 1A (PHP1A).
As not all characteristic findings in PHP1A present early in life, her short stature had been attributed to congenital hypothyroidism. Untreated hypothyroidism or interrupted treatment can reduce growth velocity and result in short stature, but she was adherent with levothyroxine, and her thyroid function tests were consistently normal. Severe congenital hypothyroidism (free thyroxine <0.8 ng/dL) can result in short stature, but early treatment significantly reduces this risk (4) and our patient did not have severe hypothyroidism. The hypothyroidism associated with PHP1A is usually mild, as in this case (elevated TSH but normal fT4). While short stature by adulthood is a major feature of PHP1A, short stature begins in childhood. According to Kinoshita et al., growth in patients with PHP1A shows a pattern of reduced growth velocity in childhood and a blunted pubertal growth spurt (5). Short bones and short stature result from the premature cessation of long bone growth, which typically begins after 5–7 years of age and most notably in the hands and feet. Declining growth velocity, no pubertal growth spurt and accelerated growth plate maturation, caused by impaired PTHrP signaling from Gs alpha deficiency, all contribute to adult short stature (6, 7, 8). The review of her growth chart (Fig. 1) reveals a growth pattern typical for PHP1A.
Pseudohypoparathyroidism
The prevalence of PHP in the United States is not well known; however, a nationwide survey conducted in Japan identified 1.2 cases of PHP per 100,000 (9). PHP is primarily a clinical diagnosis due to its variable presentation in early childhood. In a recent consensus statement, Mantovani et al. suggest that the main clinical criteria for diagnosis of PHP include a constellation of physical features (termed Albright hereditary osteodystrophy, AHO) with variable expression, including brachydactyly, stocky build, round face, early-onset obesity, ectopic ossifications and short stature relative to the height of the unaffected parent (6). Short stature alone may not be recognized as PHP, but in association with brachydactyly and other phenotypic findings, it should raise suspicion for a syndromic etiology (e.g., PHP1A, PHP1B, Turner syndrome, brachydactyly type E and brachydactyly with mental retardation) (6).
Major biochemical criteria for PHP include hypocalcemia and elevated PTH due to PTH resistance, with or without TSH resistance. Hypocalcemia and hyperphosphatemia are characteristic of both PHP and hypoparathyroidism; however, these are distinguished by the elevated PTH levels in PHP but low levels in hypoparathyroidism (6). Magnesium levels and renal function are normal (7).
Pathophysiology
All forms of PHP are caused by molecular defects that impair PTH/PTH-related peptide (PTHrP) signaling (6). Mutations in the GNAS locus on chromosome 20q13.3 are found in approximately 80–90% of patients with PHP, specifically involving exons 1–13 that encode the alpha subunit of the stimulatory G protein (Gsα) (6, 10).
The phenotype for PHP1A was first described by Fuller Albright in 1942 and is referred to as AHO (6, 10). The combination of chronic hypocalcemia and hyperphosphatemia can result in intracranial calcium deposition, commonly in the basal ganglia, referred to as Fahr syndrome (6), or deposition in the eyes, leading to cataracts (6). Dental manifestations include, but are not limited to, delay or failure of dental eruption (6). Nephrolithiasis rarely develops as hypercalciuria is uncommon because the function of the distal convoluted tubules is preserved (6). Multiple hormone resistance commonly affects TSH, which explains the congenital hypothyroidism in our patient. Resistance to gonadotropins and gonadotropin-releasing hormone (GnRH) can also occur and result in delayed puberty or hypogonadism. Resistance to growth hormone-releasing hormone can also result in GH deficiency.
Recent molecular observations help explain the variability seen in PHP. PHP1A results from a loss-of-function mutation in the maternal GNAS allele, which is normally expressed in parathyroid glands, bone, kidney, thyroid, gonads, pituitary, portions of the central nervous system and brown adipose tissue (11)..Loss of function explains the skeletal and biochemical findings characteristic of PHP1A. However, the identical mutation, when transmitted through the paternal allele, results in pseudopseudohypoparathyroidism (PPHP). PPHP manifests the same skeletal features seen in PHP1A (e.g. AHO) but is not associated with hormone resistance (11).
Parent-specific DNA methylation (epigenetic regulation) of GNAS results in variable tissue-specific expression from only one parental allele and explains the differences between PHP1A and PPHP (11). GNAS promoter regions are methylated only on the maternal GNAS allele, leaving transcription to only occur from the paternal allele (11). In contrast, the neuroendocrine secretory protein (NESP) promoter is methylated on the paternal allele and is transcribed only by the maternal allele (11). Further complicating this picture is biallelic expression of GNAS in the proximal renal tubule early in life. The paternal contribution declines as the patient ages. When maternal GNAS is mutant, this delays development of PTH resistance in the kidney, delays the onset of hypocalcemia and the elevation in PTH and can confuse the diagnosis as occurred in this case (11).
Another form of PHP, PHP1B, is transmitted as either an autosomal dominant (AD-PHP1B) or a sporadic (aporPHP1B) disorder (11). PTH resistance, hypocalcemia, hyperphosphatemia and elevated PTH levels are consistent findings (11). Resistance to thyrotropin and mild features of AHO also occur (11). However, Gsα activity is normal in erythrocytes from patients with PHP1B, which distinguishes this from PHP1A and PPHP (11).
Treatment/management
Initial therapy may require intravenous calcium salts for severe hypocalcemia. Following that, calcium supplements and the active 1,25-dihydroxy-vitamin D are necessary for long-term management (6). Correction of PTH to the upper reference range is recommended and is sufficient to enhance calcium reabsorption in the distal renal tubule (6). Overcorrection may lead to PTH suppression and should be avoided. Phosphate binders are not usually necessary for the management of long-term hyperphosphatemia (6). Serum levels of PTH, calcium, phosphorus and 1,25-dihydroxy-vitamin D should be monitored every 6 months during childhood and yearly in adults (6). More frequent monitoring may be necessary during acute illness and in adolescence. Further management includes renal imaging to monitor nephrocalcinosis and renal function (6). Patients should have regular dental care and should be educated on the clinical symptoms of hypocalcemia. Careful monitoring and replacement of other hormones, including GH and sex steroids, is necessary (if deficient).
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the work.
Funding
This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Patient consent
Written informed consent was obtained from the patient/patient’s mother for publication of this case report.
Author contribution statement
J Lynch, R Pillai, G Francis and H Gardner were involved in the clinical management of the case. R Kondetimmanahalli collected data, drafted the initial manuscript and critically reviewed and revised the manuscript. J Lynch conceptualized and designed the study and critically reviewed and revised the manuscript. G Francis and H Gardner critically reviewed and revised the manuscript. R Pillai coordinated and supervised data collection and critically reviewed and revised the manuscript for important intellectual content. All authors reviewed and approved the final manuscript as submitted.
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