A 16.5-year-old Indian female presented with secondary amenorrhea for six months. She had spontaneous thelarche at 9 years of age and menarche at 11 years of age, following which she had regular menstrual cycles for five years. She had a history of pulmonary tuberculosis 2 years prior, for which she received antitubercular pharmacotherapy for six months, after which she was declared cured. She was born at term from a non-consanguineous marriage and her perinatal history and her childhood development were unremarkable. At the time of presentation, she was a student of the tenth standard with average scholastic performance. She was lean, had no clinical evidence of hyperandrogenism and had received no treatment before her consultation. There was no history of recent weight loss, chronic stress or malnutrition and she had no history of galactorrhea, headache, seizures or visual deficit.
On examination, her height was 147 cm (between 3rd to 10th percentile; Height SDS: -1.59 SD, Indian Academy of Pediatrics 2015 growth chart references, Upper segment: Lower segment ratio = 0.9:1), her target height being 165 cm; her body weight was 55 kg (between 75th to 97th percentile, Weight SDS = + 0.51), BMI 23.8 kg/m2 (between 75th to 97th percentile, BMI SDS: +1.06). She had sinus tachycardia with a heart rate of 120/min and had stage 1 hypertension with clinic BP of 136/88 mm Hg. There was mild scoliosis with convexity to the right. She had a grade 1b goitre and grade 2 acanthosis nigricans. She had multiple cafe-au-lait macules with dimensions ranging from 5 to 25 mm distributed over her arms, thighs and backs (Figure 1), multiple lentigines over her face (Figure 2) and axillary freckling. She had cubitus valgus (Figure 3) and short fourth metacarpals. Systemic examination including cardiovascular, neurological, respiratory and abdominal examination revealed no abnormalities. Tanner's sexual maturity rating for her was B5P2A0 and she had unambiguous female genitalia with no clitoromegaly or hirsutism.
Initial investigations aimed at evaluating the etiology for short stature revealed normal results for most routinely tested parameters (Table 1). X-ray of her left wrist and hand showed a bone age of 17 years, which corroborated her chronologic age (Greulich and Pyle's atlas). She had subclinical hypothyroidism with TSH 5.6 mIU/ml, normal free T4, and TPO antibody was positive. She had evidence of primary ovarian failure with low estradiol inspite of high FSH and LH.
The clinical findings of proportionate short stature, secondary amenorrhea, cubitus valgus, multiple lentigines over face, scoliosis, hypertension and high FSH levels prompted further evaluation for Turner Syndrome. Karyotype of peripheral blood cells revealed mosaic TS with isochromosome Xq - 45, X [27]/46,X,i(X)(q10)[03] (Figure 4). Following a diagnosis of TS, relevant investigations to screen for comorbidities and complications known to be common in TS were done (Table 1).
The index case had a total of six cafe-au-lait macules out of which only four had diameters exceeding 15 mm. She also had evidence of axillary freckling. There were no subcutaneous or plexiform neurofibromata and upon slit lamp examination, she had no Lisch's nodules or distinctive osseous lesions like sphenoid dysplasia or tibial pseudoarthrosis. There was no known history of neurofibromatosis in any of her first-degree family members. Thus, she did not fulfil the classic criteria for a diagnosis of NF1, which was chiefly due to the smaller size of her cafe-au-lait macules than the cut-off of 15 mm required for diagnosis in the post-pubertal age. However, due to strong clinical suspicion, clinical exome sequencing was done which revealed a heterozygous single base pair deletion in exon 21 of the NF1 gene (chr17: g.29556477delA), which was a pathogenic variant consistent with NF1. Home blood pressure monitoring confirmed persistent stage 1 hypertension. Screening for phaeochromocytoma through 24-hour urinary fractionated metanephrines (metanephrines and normetanephrines) was done with normal results. MRI of the brain revealed no optic nerve glioma or CNS tumours.
She was started on estradiol valerate 2 mg daily and medroxyprogesterone 10 mg daily for 10 days every month which induced regular menstrual cycles. She was counselled regarding the poor prospect of future fertility and offered the option for oocyte cryopreservation. During therapy with estrogen and progesterone, she was closely monitored for any new appearance of neurofibromata or worsening of visual acuity or headache for the possibility of optic glioma expansion though she did not develop any of these in her two years of follow-up. She was advised against daily estrogen-progesterone combined pills as a therapeutic strategy to reduce progesterone exposure since there is evidence suggesting the permissive role of progesterone on neurofibroma expansion.
Her bone age was 17 years and X-ray of her knees revealed fusion of her upper tibial and distal femoral epiphyses and therefore she was not initiated on recombinant growth hormone therapy. She was given calcium 500 mg/day and cholecalciferol 2000 IU/day for bone health. She was started on metoprolol 25 mg once daily for her hypertension and sinus tachycardia to achieve a target heart rate of 60/min and SBP less than 130 mm Hg. She was periodically monitored with echocardiography and cardiac MRI for aortic root diameter and aortic size index, annual testing of liver function and metabolic profile, pure tone audiometry and BMD-DXA.
Written informed consent was obtained from the patient and her parents for publication of this case report and images of the patient and her genetic tests.