Case 1: An eight-year-old girl with short stature

An eight-year, three-month-old girl was referred for slowed growth. Her parents reported three years of growth arrest, during which she continued to wear the same size of clothing and fell well below the third percentile for height (Figure 1). Previous growth velocity had been normal, with height plotting along the 50th percentile and midparental height at the 50th percentile. Review of systems was negative for headaches, vomiting or vision changes. There was no fatigue, cold intolerance, constipation, or skin or hair changes. Appetite and weight were normal. There were no academic concerns. Breast development began at eight years of age with scant pubic hair that developed shortly thereafter. The patient was premenarchal. Medical history and functional inquiry were noncontributory. She had been born at term weighing 3.7 kg. Patient's growth parameters demonstrating significant short stature and slowed growth velocity. Measures plotted on the Canadian Pediatric Endocrine Group growth chart using WHO reference data. Growth chart reproduced with permission from the Canadian Pediatric Endocrine Group Parental pubertal timing was within normal limits. Family history was negative for short stature, endocrine or autoimmune conditions. Examination revealed a nondysmorphic, proportionate child who appeared much younger than her chronological age. Height was 9 cm below the third percentile (−2.9 SDs), weight was at the third percentile and body mass index at the 25th percentile. Upper:lower segment ratio, arm span, vital signs, optic fundi and visual fields were normal. There was no thyromegaly, scoliosis or features of Turner syndrome. Breast and pubic hair development were Tanner stage 2. Investigations completed by the referring physician revealed a thyroid-stimulating hormone (TSH) level of 1.3 mIU/L (normal range 0.5 mIU/L to 5 mIU/L) and free thyroxine (fT4) 8.2 pmol/L (normal range 8.7 pmol/L to 16 pmol/L). Complete blood count, electrolyte, glucose, creatinine, liver enzyme and tissue transglutaminase antibody levels were normal. Her bone age at seven years and eight months of age was three years and six months, with an SD of 8.3 months. Further testing revealed the diagnosis. Growth hormone (GH) stimulation testing with arginine and clonidine revealed peak GH levels of only 2.4 μg/L and 1.7 μg/L, respectively (normal ≥5.6 μg/L). Although random luteinizing hormone and follicle-stimulating hormone levels were only 1 IU/L and 5 IU/L, respectively, a gonadotropin-releasing hormone stimulation test demonstrated a peak leuteinizing hormone level of 11 IU/L, confirming gonadotropin-dependent (ie, central) puberty. Additional pituitary testing showed insulin-like growth hormone-1 was 107 μg/L (88 μg/L to 474 μg/L), TSH 1.60 mIU/L (0.5 mIU/L to 5 mIU/L), fT4 8.6 pmol/L (8.7 pmol/L to 16 pmol/L) and free tri-iodithyronine 4.7 pmol/L (3.3 pmol/L to 6.0 pmol/L). Cortisol and prolactin levels at 08:00 were normal. She was formally diagnosed with GH deficiency (GHD), central precocious puberty and central hypothyroidism. Magnetic resonance imaging of her head revealed a 1.1 cm × 1.0 cm × 1.3 cm loculated, cystic sellar lesion with suprasellar extension consistent with craniopharyngioma. She was referred to neurosurgery and to ophthalmology for visual field testing. GH and thyroxine replacement were initiated, in addition to leuprolide (Lupron Depot, Abbott Laboratories, Canada) to halt pubertal progression and preserve final adult height. Although short stature is technically defined as an absolute height ≤3rd percentile for age and sex, a child's growth velocity (GV) is an even stronger indicator of their general health. In prepubertal children >3 years of age, a normal GV is 5 cm/year to 7 cm/year measured over at least a four- to six-month period (1). A subnormal GV, manifested in downward crossing of percentiles, can be one of the earliest indicators of disease and is a key feature distinguishing pathological from physiological causes of short stature. Physiological causes include familial short stature, and constitutional delay of growth and puberty (CDGP). Familial short stature is secondary to a reduced genetic height potential. Features of CDGP include later-than-average pubertal development, delayed bone age and, frequently, a family history of CDGP. Importantly, in both physiological conditions, GV is normal and predicted adult height is within two SDs of midparental height (approximately 8.5 cm). In the present case, the extremely slow GV and deviation of current height from genetic potential were highly suspicious for underlying pathology. The differential diagnosis of pathological short stature is broad and includes uncontrolled chronic disease, growth-inhibiting medications, genetic/chromosomal disorders, skeletal dysplasias and intrauterine growth restriction without catch-up growth. In the present case, these causes were highly unlikely given the negative history, normal developmental history, proportionate anthropometric measures and absence of dysmorphic features. Maintenance of weight percentiles despite slowed growth is inconsistent with chronic disease and suggests an endocrine cause. Primary hypothyroidism is the most common endocrine cause of short stature. Others include GHD, Turner syndrome, central hypothyroidism and Cushing syndrome. GHD can be congenital or acquired, and isolated or associated with other pituitary endocrinopathies. Congenital GHD may be secondary to perinatal asphyxia or mutations in genes directing pituitary development (Pit-1, Prop-1, Lhx-3/Lhx-4 and Hesx-1), or encoding key components of the axis such as the GH gene. Acquired GHD is most commonly idiopathic, but can also arise from any lesion affecting the anterior pituitary, pituitary stalk or hypothalamus. These include tumours (eg, craniopharyngioma, germinoma, glioma), trauma, central nervous system infections, radiation, surgery or infiltrative disorders such as histocytosis. Acquired GHD presents with significant growth failure with maintenance of weight percentiles and delayed bone age. Insulin-like growth hormone-1 levels may be low, especially in older children. Congenital GHD may present with midline anomalies, micropenis, neonatal hypoglycemia as well as growth failure in infancy – typically after six months of age. GH stimulation testing with two stimuli is the gold standard to confirm GHD. Random GH levels are of no value given the pulsatile nature of GH secretion. In addition to GHD, clues suggesting a pituitary etiology in the present case include a low fT4 level with an inappropriately normal TSH level, and evidence of central puberty with both estrogen and androgen signs (breast development and pubic hair, respectively). Although normal puberty onset in girls occurs between eight and 13 years of age, central puberty at a bone age of three years and six months with growth deceleration is clearly abnormal. Although peripituitary masses usually have an inhibitory effect on hormone secretion, a stimulatory effect can be observed (2). Interestingly, in this patient, although the mass inhibited GH and TSH secretion, causing GH deficiency and central hypothyroidism, respectively, gonadotropin secretion was stimulated, causing central precocious puberty. Although short stature is defined as an absolute height ≤3rd percentile for age and sex, a child's GV is an even stronger indicator of their general health. Short stature can be due to physiological or pathological etiologies. Pathological causes should be suspected when GV is slow (<5 cm/year to 7 cm/year from three years of age to puberty) or predicted final adult height is >8.5 cm from mid-parental height. GHD can be due to a variety of congenital or acquired causes. Presenting manifestations include postnatal growth failure and delayed bone age, with confirmation by GH stimulation testing. Peripituitary lesions can have inhibitory or stimulatory effects on pituitary hormone secretion. Detection of any pituitary hormone abnormality necessitates screening for other pituitary hormone abnormalities and brain imaging.

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