Turner syndrome and neurofibromatosis type 1: the unusual combination of two common genetic disorders

Background

Neurofibromatosis type 1 (NFT1) or Von Recklinghausen's disease results from germline mutations in the tumor suppressor gene NF1. It is an autosomal dominant disease, with variable expression, a high rate of spontaneous mutations and an incidence of 1:2500 to 1:3000 (1). The diagnosis can usually be made through the clinical criteria defined by the National Health Institute. The patient must meet at least two criteria: ≥6 café-au-lait spots (>5 mm diameter in pre-pubertal individuals; >15 mm in post-pubertal individuals); ≥2 neurofibromas of any type, or 1 plexiform neurofibroma; freckling in axillary or inguinal regions; optic glioma; ≥2 Lisch nodules (iris hamartomas); a distinct osseous lesion (sphenoid dysplasia; tibial pseudoarthrosis); ≥1 first degree relative with type 1 neurofibromatosis (2). More recently, the detection of a pathogenic germline NF1 variant in heterozygosity in normal tissue cells has been proposed as an additional criterion (3). About 12% of NFT1 patients present a Noonan-like phenotype with short stature, short broad neck and hypertelorism (4). In fact, a distinct entity called neurofibromatosis-Noonan syndrome (NFT1-NS) has been described (5).

Turner syndrome (TS) is a sex chromosome disorder, characterized by the complete or partial absence of one of the X chromosomes, that affects about 1:2000 newborns (6). It is associated with gonadal dysgenesis, retarded growth and a characteristic phenotype that has some similarities with that of NS (7).

The coexistence of NFT1 and TS has only been reported in a few patients, with less than ten cases described in the literature (5). We report a rare case of coexistence of both syndromes and discuss its practical implications.

Case presentation

A 16-year-old girl, with a prior diagnosis of NFT1, was referred to Endocrinology appointments for the etiological study of primary amenorrhea.

The child had been born from a pregnancy with adequate surveillance, with intrauterine growth restriction. The delivery was eutocic at 37 weeks, and at birth, she weighed 2210 g and 44 cm in length.

In her first months of life, several abnormalities were detected. A suspicious phenotype with large and low-implantation earlobes, short neck, and hypertelorism was noted. At 5 months of age, congenital hip dysplasia was diagnosed and treated conservatively. When she started walking, at 15 months of age, dyspnoea and peripheral cyanosis were described by her parents. This led to the diagnosis of an ostium secundum persistent interatrial communication which was surgically corrected when she was 18 months old. During her first years of life, she also had failure to thrive. After correction of the interatrial communication, there was a slight improvement in weight (she crossed from below the 3rd to 25th percentile), with no significant improvement in height (which maintained below the third percentile). Developmental delay and attention deficit hyperactivity disorder were also diagnosed, and the child required learning support. Several otorhinolaryngological abnormalities, including nasal obstruction and sleep apnoea due to adenoid hyperplasia, were detected precociously and the patient was submitted to adenoidectomy when she was 27 months old. During her childhood, she had several middle-year infections, and at the age of 6, she was submitted to plasty of the auricular cartilage.

There was family history of NFT1 in her father and grandfather, therefore there was a high level of suspicion when several café-au-lait spots were detected. At age 7, due to clinical suspicion during an ophthalmologic examination, magnetic resonance was requested which described optic chiasm and optic nerves thickening mostly on the left, probably translating to an optic nerve glioma. (Fig. 1

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Phenotypical characteristics suggestive of NFT1: (A) black arrow points toward a café-au-lait spot and the red arrow signals a neurofibroma; (B) freckling in the axillary region; (C) magnetic resonance showing optic nerve thickening consistent with the presence of an optic glioma (red arrow). NFT1, neurofibromatosis type 1.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2022, 1; 10.1530/EDM-22-0226

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At age 16, due to the absence of pubertal development, she was observed in endocrinology appointments for the first time. She was 131 cm tall, weighed 34 kg and lacked secondary sexual characteristics. Besides the above-mentioned phenotypical characteristics, she also displayed several cutaneous neurofibromas. A bone evaluation had been performed and revealed a bone age of 12 years and 3 months for a chronological age of 16 years and 3 months with a 75% maturation delay.

Investigation

A comprehensive study was requested. Laboratory study revealed normal kidney function, discrete elevation of liver enzymes – alanine aminotransferase 152 U/L (<34); aspartate aminotransferase 36 U/L (<31); alkaline phosphatase 164 U/L (47–119) and gamma-glutamyl transferase 89 U/L (4–24) – an A1C of 5.8% and a lipid profile within the reference range. Evaluation of the anterior pituitary function was indicative of hypergonadotropic hypogonadism – FSH 152 mUI/mL (<9.6), LH 27 mUI/mL (<12), estrogen 18 pg/mL (10–200) and progesterone <0.2 mg/mL (<1.5). Abdominal and pelvic ultrasound showed a horseshoe kidney and a pre-puberal configuration of the uterus, a small right ovary and the left ovary was not visualized. A skeletal x-ray study revealed dextroconvex scoliosis in the dorsal spine and rectification of the physiologic lordosis in the lumbar spine.

Due to the presence of a suspicious phenotype, (Fig. 2

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Phenotypical characteristics suggestive of TS with large and low-implantation earlobes, short neck and hypertelorism.TS, Turner syndrome.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2022, 1; 10.1530/EDM-22-0226

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Treatment

The patient was initiated on hormone replacement therapy with estradiol and dydrogesterone with some development of secondary sexual characters. Growth hormone was not initiated because, due to her bone age, the patient did not fill the criteria for reimbursed treatment in our country and there were also concerns regarding cardiac implications.

Outcome and follow-up

She is currently 27 years old and has reached a height of 135 cm (significantly below her target family height of 165 cm) but has a normal BMI (21.9 kg/m²). During the follow-up, she presented two HbA1c values of 5.8%; however, a return to normoglycemia was achieved through lifestyle measures. Heterogeneous echogenicity of the thyroid gland and positive anti-peroxidase antibodies were detected, making the diagnosis of autoimmune thyroiditis. The patient has been kept under multidisciplinary follow-up and no further endocrine abnormalities have been found so far.

Discussion

We present a rare case of coexistence of NFT1 and TS. In retrospect, there were several leads for the diagnosis of TS in the first years of life: the suggestive phenotype, difficulty thriving, cardiac abnormalities, adenoid hyperplasia, medial ear infections and outer ear deformities. However, the fact that NFT1 can be associated with a Noonan-like phenotype was likely considered an explanation for the child’s phenotype. Comparing to NFT1, NFT1-NS presents with additional phenotypical characteristics of NS, such as short stature, short broad neck, low-set ears and ocular hypertelorism (4). These features overlap with the phenotype of TS that the patient presented. Short stature has been described in 8–33% of NFT1 patients (8). Atrial septal defects are most frequently associated with TS (7), but its prevalence is also increased in NS (9) and in NFT1 (10). Several features of TS are also common in NS, but have not been specifically described in the NFT1-NS phenotype. Figure 3 depicts which of the patient’s clinical features fit in each of the syndromes.

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Illustration of the patient’s features attests which fit in the diagnosis of NFT1-NS syndrome and which features are only explained by the coexistence of Turner Syndrome. Some aspects have also been reported in NS but have not specifically been described in NFT1-NS (marked with *). Others have only been frequently described in Turner Syndrome. NFT1, neurofibromatosis type 1; NFT1-NS, neurofibromatosis-Noonan Syndrome; TS, Turner syndrome.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2022, 1; 10.1530/EDM-22-0226

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All the above-mentioned factors probably contributed to the late diagnosis of TS. NFT1 may be associated with precocious puberty, especially in cases such as this with chiasmatic involvement with the glioma (8). Pubertal delay is less frequently reported, and it was this factor which motivated the referral of this patient. Regardless of the presence of a tumor affecting the chiasm, NFT1 may rarely be associated with hypogonadotropic hypogonadism. The finding of hypergonadotropic hypogonadism, however, is not expected, and its investigation outside of the context of NFT1 was a red flag of the presence of another entity.

Both TS and NFT1 require multidisciplinary follow-up, with special attention to the most common comorbidities and complications. The additional diagnosis of TS adds several risks to this patient, leading to increased morbidity and reduced lifespan (estimated about 13–15 years compared to the general population). This is mainly due to the augmented risk of cardiovascular diseases (responsible for 50% of the excess mortality), autoimmune endocrine diseases (such as diabetes mellitus and thyroiditis), osteoporosis, anemia and diseases of the digestive system (7).

In this case, the coexistence of NFT1 led to a delay in the diagnosis of TS. As several phenotypical aspects may be common to different syndromes, distinguishing which characteristics do not fit in a particular syndrome and considering the presence of a second one certainly represents a diagnostic challenge. However, especially in the setting of common genetic disorders, more than one may rarely coexist. Adequate surveillance of these patients is essential, as they have a greater cumulative risk of serious manifestations. The presented case has a longer follow-up than the cases of TS and NFT1 previously reported in the literature which allows the evaluation of the impact of the disease on adult life and attests to the possibility of ameliorating these consequences through an adequate follow-up.