Exacerbated mini-puberty of infancy in an ex-extreme preterm girl

Background

Vaginal bleeding is uncommon in infancy but has a wide differential diagnosis and can represent pathological conditions, such as central precocious puberty (CPP), or just a variation of normal.

It may happen shortly after delivery as a physiological result of the sudden withdrawal of placental hormones, which is clinically evident in about 3%–5% of newborns, and occurs microscopically in 25%–60%.1 This is called mini-puberty of infancy and corresponds to a transient hypothalamus–pituitary–gonadal (HPG) axis activation, usually self-limited, with the highest incidence around the 6–8th week after delivery. Hormonal profile tends to normalise in 6–9 months.

Preterm infants can present with a symptomatic form of mini-puberty as a result of the immaturity of peripheral tissues and endocrine regulation systems.

With the improvement of survival rates for extreme premature infants, the clinicians need to be aware of the hormonal particularities of this group of patients, being able to recognise variants of normal.

Case presentation

A 4-month-old girl (6 weeks postmenstrual age), born at 26 weeks of gestation, presented with a 2-day history of vaginal bleeding. Abdominal pain and irritability were also noted. Other symptoms, recent trauma and use of medication or cosmetic products were denied.

The family history was irrelevant. Family history of precocious puberty in first-degree relatives was denied. Her sister was healthy.

She was born by eutocic delivery, with an Apgar score of 6/8/8 (1st, 5th and 10th minutes). At birth, her weight, length and cephalic perimeter were 760 g (P10-50, according to Fenton preterm growth charts), 32 cm (P10-50) and 21.7 cm (P50), respectively. She had been diagnosed with grade II–III respiratory distress syndrome, surgically closed patent arterial duct, grade II bilateral periventricular-intraventricular haemorrhage, right vocal cord paralysis and laryngomalacia.

At hospital admission, no breast development, pubic hair or clitoromegaly were observed. No café-au-lait spot was identified. Abdominal palpation and the remaining physical examination were unremarkable. She had psychomotor retardation, short stature and facial abnormalities.

The presence of an isolated vaginal bleeding led us to consider a benign pubertal variant and to adopt expectant management.

Vaginal bleeding progressively improved and resolved in 6 days, and the patient was discharged on the 8th day of admission.

Investigations

At admission, luteinising hormone (LH), follicle-stimulating hormone (FSH) and oestradiol were 17.67 mIU/mL, 4.68 mIU/mL and 68.70 pg/mL, respectively (table 1). Carcinoembryonic antigen (CEA), alpha-fetoprotein and human chorionic gonadotrophin levels were 1.36 ng/mL, 1292.6 ng/mL and 1.2 mIU/L, respectively. There was no established preterm (<28 weeks) reference values for alpha-fetoprotein levels. On the 10th day of admission, alpha-fetoprotein was 677 ng/mL. Thyroid function was normal: thyroid stimulating hormone (TSH) of 0.78 mIU/L and free thyroid hormone (FT4) of 1.09 ng/dL.

An abdominal and pelvic ultrasonography revealed a right ovarian cyst with 43 mm of diameter (figure 1) and endometrial hyperplasia. Utero dimensions were 51×14×20 mm, high for age (table 1). A cranioencephalic MRI (CE-MRI) did not reveal alterations.

Concerning psychomotor retardation, short stature and facial abnormalities, an exome sequencing was made. A pathogenic heterozygous mutation in ANKRD11 (Glu800Asnfs*62) was identified, making the diagnosis of KBG syndrome. Also, a heterozygous mutation in RAD51D (Agr252*) was incidentally detected.

Differential diagnosis

Attending to the presence of an isolated vaginal bleeding, a normal variant puberty was considered. However, the presence of pelvic ultrasonographic alterations and extremely elevated LH levels cast doubt on this hypothesis. Furthermore, the paucity of normative data for serum LH, FSH and oestradiol levels in female-born preterm makes the exact differentiation between benign and pathological conditions more difficult.

The differential diagnosis of vaginal bleeding includes genital tract trauma or infection, foreign body and sexual precocity.2

In this case, clinical history and physical examination did not suggest trauma. There was no reference to fever or vaginal discharge, so genital tract infection and foreign body were unlikely. Considering sexual precocity, it may have a central or peripheral origin.

Peripheral precocious puberty (PPP) is caused by an excessive secretion of sex hormones endogenously produced (gonads, adrenal gland, ectopic production) or from an exogenous origin, leading to a suppression of gonadotrophin levels.2 3 The ovarian cyst showed by ultrasonography could be responsible for the elevated oestradiol levels. However, the presented patient also had elevated gonadotrophin levels, making PPP improbable.

The use of medication or cosmetic products that contain exogenous steroids was denied. Furthermore, the abdominal ultrasonography did not show adrenal gland alterations. To investigate a possible sex steroid-secreting tumour, CEA levels were measured and were normal for age. Severe and prolonged primary hypothyroidism may also cause PPP, probably due to stimulation of FSH receptors by elevated levels of TSH.2 3 Our patient’s thyroid function was normal. McCune-Albright syndrome is a rare disorder characterised by a triad of PPP, irregular café-au-lait spots and fibrous bone dysplasia.2 During this child’s follow-up, an isolated café-au-lait spot was identified. Nevertheless, at that time, she was asymptomatic and the hormonal levels were normalised, so this skin lesion was considered an innocent finding.

The laboratory investigation demonstrated, in addition to elevated oestradiol levels, gonadotrophin levels in pubertal range, that is, an early maturation of the HPG axis, suggesting CPP.2 3 The idiopathic cases of CPP prevail, followed by central nervous system (CNS) lesions, which were excluded by a normal CE-MRI in our patient.2 In CPP, pubertal development occurs before the expected age, but usually respects the normal sequence, with breast and pubic hair development preceding ovarian and utero enlargement.2 3 These children have gonadotrophins in pubertal range, as occurred in our patient.2 However, she presented with vaginal bleeding with no other signs of pubertal development, making CPP improbable. Thereby, none of the presented hypotheses fitted perfectly in this case. The absence of clinical worsening enabled us to adopt expectant management.2 4 5

KBG syndrome is an autosomal dominant disorder characterised by facial and skeletal abnormalities (including short stature) and psychomotor retardation, which were reported in this girl.6

Outcome and follow-up

Follow-up appointments with a paediatric endocrinologist and a paediatric surgeon were made. One month after discharge she exhibited signs of breast development, with a Tanner stage M2. No pubic or axillar hair was observed. The child had a total of five episodes of vaginal bleeding, each lasting less than a week and almost all associated with irritability and abdominal pain. The intervals between episodes were approximately 3 weeks.

By the 18th week of postmenstrual age, no more episodes of vaginal bleeding were reported and hormonal levels normalised. The ultrasonography revealed an infantile uterus without the previous signs of endometrial impregnation and normal-sized ovaries with several follicles below 6 mm (table 1).

At the postmenstrual age of 7.5 months, it was noted an isolated abdominal café-au-lait spot with 1.5 cm of diameter. No progression of pubertal development was registered during an 8-month follow-up period.