Joubert syndrome with multiple pituitary hormone deficiency

Abstract

Joubert syndrome (JS) and JS-related disorders are a group of developmental delay, multiple congenital anomalies and complex midbrain–hindbrain malformations. A few cases of JS with multiple pituitary hormone deficiency (MPHD) have been reported in literature. Here, we presented an unusual presentation of JS in a newborn with MPHD. This case is intended to draw attention to the rare association of JS and MDPH by increasing the awareness of this syndrome.

Background

Joubert syndrome (JS) and JS-related disorders (JSRD) are a group of developmental delay, multiple congenital anomaly syndromes in which the complex midbrain–hindbrain malformation is visible on brain imaging.¹ This clinically and genetic heterogeneous syndrome is related to the dysfunction of a subcellular organelle, the primary cillium which make JSRD part of ciliopathies.¹ The incidence of JSRD may range between 1/80 000 and 1/100 000 live births.² The most descriptive finding of JSRD on MRI is molar tooth sign (MTS).² In JS, MTS is seen in about 85% of patients.³ The term JSRD is coined to all conditions sharing the MTS and this neuroradiological sign now represents the mandatory criterion to diagnose JSRD.² JSRD is characterised with hypotonia, abnormal ocular movements (mainly ocular motor apraxia, nystagmus and strabismus), occasionally changes in respiratory pattern occuring, as early as the first few months of life.⁴ Renal, hepatic and skeletal abnormalities can also be observed. At the neuropathological level, MTS results from the hypoplasia and dysplasia of the cerebellar vermis, pontine and medullary structures, and the absence of decussation of the superior cerebellar peduncles and the pyramidal tracts.^{2 4} Brain imaging will also reveal possibly associated central nervous system defects, which can include ventriculomegaly, occipital meningoencephalocele, polymicrogyria, periventricular nodular heterotopia, hypothalamic hamartoma, corpus callosum defects, hippocampal malformations, morphological brainstem abnormalities and rarely absence of pituitary gland, which affect mostly the midbrain and tectum.² Recently, next-generation sequencing strategies have caused several genes been identified and characterised at the pathophysiological level. Thirty-three different mutations have been discovered to cause JSRD until today.^{5 6} However, defined mutations could only be detected in 50% of patients with JSRD.² Only a few JSRD patients with multiple pituitary hormone deficiency (MPHD) have been reported in literature.^7–9 Our patient is a rare case of JS in associated with MPHD. It was presented to draw attention to this rare association. In addition, we aimed to emphasise that JSRD should be considered in the differential diagnosis of patients with syndromic findings and MPHD or conversely when the MTS is detected on MRI, MPHD should be kept in mind and hormonal profile should be checked.

Case presentation

Endocrinological evaluation was requested for a 13-day-old baby with the symptoms of hypoglycaemia and micropenis. He was born at term, by caesarean section with meconium aspiration and he was intubated as a result of respiration distress. He was 3420 g (0.04 SD) in weight, but birth height is unknown. There was no consanguinity between parents. On physical examination, postaxial polydactyly in both right hand and right foot (figure 1), micropenis and bilateral cryptorchidism were detected. The first endocrinological tests carried out when the patient was in neonatal intensive care unit and he was seen in outpatient clinic in 2 months after he was discharged.

Figure 1.

Postaxial polydactyly of right hand and right foot.

Investigations

At 2 months of age, the patient was 3790 g in weight (−2.2 SD), 51.8 cm in height (−2.2 SD) and had a head circumference of 38.8 cm (−1.4 SD) (table 1). Tests for congenital metabolic diseases were normal. Levels of adrenocorticotropic hormone (ACTH) (<5 pg/mL), cortisol (0.07 µg/dL) and gonadotropins (luteinising hormone/follicle-stimulating hormone <0.1 mIU/mL) were low. Hypothyroidism was also detected (free thyroxine: 0.55 ng/dL, thyroid-stimulating hormone (TSH): 5.98 mIU/L) (table 2). Karyotype was 46,XY. On pelvic and scrotal ultrasonography, two testes were seen in the inguinal canal and also the internal structure of each testis was observed as normal. Cerebellar vermis and sella hypoplasia, pituitary agenesis and MTS were seen on cranial and sella MRI (figures 2 and 3). The short-time human chorionic gonadotropin (1500 U/m²/day, intramuscular injection, 3 days) test was done. Basal and stimulated testosterone levels were low whereas testosterone precursors were normal (table 2). Growth hormone (GH) stimulation tests were performed at 6 months of life because of the deceleration in growth rate and GH deficiency was detected (table 2).

Table 1.

Evaluation of growth pattern of the patient at follow-up

	2 months	6 months	1 year	1.5 years (at the onset of GH treatment)	2.5 years	3 10/12 years
Weight (kg)	3.8	5.2	5.5	6.9	7	9.7
Weight SD	−2.2	−2.5	−4.6	−3.8	−6.5	−4.6
Height (cm)	51.8	56	60	62	72	84
Height SD	−2.2	−3.5	−5.2	−5.9	−5.3	−4.5
Head circumference (HC) (cm)	38.8	40.5	41.2	41.9	44.2	46.2
HC SD	−1.4	−1.8	−4.0	−4.3	−3.6	−3.1
BMI (kg/m2)	14.1	16.5	15.2	17.9	13.5	13.7
BMI SD	−0.7	−0.5	−1.3	0.7	−2.3	−1.7

BMI, body mass index.

Table 2.

Hormonal findings of the patient at diagnosis and at follow-up

	Age	Basal values	After stimulation	Normal ranges
fT4 (ng/dL)	13 days	0.55	–	0.8–1.8
TSH (mIU/L)	13 days	5.98	–	0.35–7.5
Cortisol (µg/dL)	13 days	0.07	–	2–11
ACTH (pg/mL)	13 days	<5	–	6–48
LH (mIU/mL)	13 days	<0.1	–	0.02–7
FSH (mIU/mL)	13 days	<0.1	–	0.16–4.1
Testosterone (ng/mL)	13 days	<0.025	–	0.75–4
IGF-1 (ng/mL)	9 months	<25	–	55–237
IGFBP-3 (mg/L)	9 months	<0.5	–	0.7–3.6
ACTH test (low dose)
Cortisol (µg/dL)	14 days	0.07	5.6	18<
HCG test (1500 U/m2/day, intramuscular injection, 3 days)
Testosterone (ng/mL)	1 month	<0.025	0.25	0.75–4 (basal T range in full term male newborn)
17 OH P (ng/mL)		1.2	0.4	0.11–10.2
A4 (ng/mL)		3.2	0.13	0.08–0.5
DHT (pg/mL)		125	81.4	250–990
DHEA-S (µg/dL)		–	3.4	0.88–3.56
GH stimulating tests (peak GH, ng/mL)
Clonidine	9 months	0.2	1.1	>7
L-DOPA	nine mos	0.3	0.9	>7

17 OH P, 17-hydroxyprogesterone; A4, androstenedione; ACTH, adrenocorticotropic hormone; DHEA-S, dehydroepiandrosterone sulfate; DHT, dihydrotestosterone; FSH, follicle-stimulating hormone; fT4, free thyroxine; GH, growth hormone; HCG, human chorionic gonadotropin; L-DOPA, levodopa; LH, luteinising hormone; T, testosterone; TSH, thyroid-stimulating hormone.

Figure 2.

Molar tooth sign. Axial Fluid Attenuated Inversion Recovery (FLAIR) MRI of the brain showed elongated superior cerebellar peduncles giving the appearance of MTS to midbrain and superior peduncles with cerebellar vermis hypoplasia. MTS, molar tooth sign.

Figure 3.

Sagittal T1-weighted MRI showed pituitary agenesis.

Differential diagnosis

Developmental delay, dysmorphism and cranial imaging findings were suggestive of JS in the patient. MPHD (GH, ACTH, TSH, gonadotropin deficiency) was associated with JS in the patient (table 2). Renal ultrasonography was normal. Vision and hearing examinations were normal. Skeletal survey was normal except for polydactyly. The patient was diagnosed as JS consequently. To exclude other possible genetic causes of MPHD, HESX1, LHX3 and LHX4 gene mutation analyses were performed and no mutation was observed.

Treatment

Steroid and then l-thyroxine replacement treatment were started respectively after the first evaluation of 13-day baby. Penile length and diameter were increased with applied local dihydrotestosterone. GH treatment was started at 1.5 years of age in a dose of 0.03 mg/kg/day.

Outcome and follow-up

The patient’s treatment and follow-up is still ongoing. Last assessment was done at 3 10/12 years; weight was 9.7 kg (−4.6 SD), height was 84 cm (−4.5 SD) and head circumference was 46.2 cm (−3.1 SD) (table 1). His bone age was 2.5 years at last assessment. He currently receives GH, l-thyroxine and hydrocortisone replacement treatments. His growth rate is controlled every 6 months and sex steroid treatment is planned in the adolescence period.

Discussion

In this study, we presented an unusual presentation of JSRD in a newborn who had panhypopituitarism. Isolated GH deficiency or gonadotropin deficiency, hypothyroidism and obesity associated with JS have been reported.^7–11 Pituitary agenesis may also be rarely associated with this syndrome.^7–9 Until today, a total of four cases, including two siblings have been reported as a combination of JS and pituitary agenesis with MPHD.^7–9 By Al-Ghazali et al, two siblings had been shown to have pituitary agenesis and MPHD associated with JS.⁷ Wolf et al analysed 56 patients with a diagnosis of JS and 1 patient who had pituitary agenesis with MPHD has been reported.⁹ The two siblings were presented with the older terminology as orofaciodigital syndrome by Al-Ghazali et al.⁷ MPHD accompanied by this syndrome had been observed in these cases. GH, ACTH and TSH deficiencies were determined in both two siblings. Both two siblings (one was girl) had dysmorphic appearance with ptosis. Additionally, in male sibling, postaxial polydactyly in bilateral hands and one foot, as well as bilateral undescended testes and micropenis were observed.⁷ Both cases, whose heights were <3 percentile, were initiated l-thyroxine, hydrocortisone and GH replacement therapy, similar to our case (table 3). Wolf et al reported a 7-year-old male patient with a diagnosis of JS and pituitary agenesis who was the third JS case with MPHD reported in the literature.⁹ l-thyroxine, hydrocortisone and GH replacement were started as a result of detection of TSH, ACTH and GH deficiency in that case. This 7-year-old patient differed from our patient and the previously identified two siblings because of hepatic and renal involvement. Recently, JSRD and panhypopituitarism in a newborn who is Turkish, was also reported.⁸ Early diagnosis of MPHD is extremely important for preventing morbidity and mortality. Late initiation of thyroid hormone replacement leads to mental retardation and cortisol deficiency can be fatal in case of severe stress if treatment is not started. On GH treatment, a significant increase in the annual growth rate and acceleration in somatic growth was seen in our patient.

Table 3.

Findings of patients diagnosed with both JS and MPHD in the literature

	Age at diagnosis/gender	Clinical signs	Hormone deficiencies	Associated findings	References
1*	3-year 5 months/female	Prominent forehead, ptosis in left eye, limitation of rotation of the left eye, small left pupil and missed light reflex in left pupil, teething delay, short stature	GH, TSH, ACTH	Hypoplasia of sella tursica, empty sella, cerebellar vermis hypoplasia	6
2*	5 months/male	Prominent forehead, bilateral ptosis, laterally deviated eyeballs, restriction of eyes movement and unresponsive pupils to light, postaxial polydactyly in two hands and one foot, micropenis, bilateral undescended testes, short stature	GH, TSH, ACTH	Corpus callosum and cerebellar vermis hypoplasia, hypoplastic and empty sella turcica	6
3	7 years/male	Mental retardation, esophageal varices, hepatic fibrosis, renal failure, abdominal myofibroblastic tumour	GH, TSH, ACTH	Pituitary agenesis, cerebellar vermis aplasia	8
Our patient	2 months/male	Postaxial polydactyly in right hand and foot, bilateral undescended testes, micropenis	GH, TSH, ACTH, gonadotropins	The cerebellar vermis hypoplasia, thickening of the superior cerebellar peduncle, brain stem molar view, hypoplasia of sella turcica, pituitary agenesis

*Siblings 1 and 2.

ACTH, adrenocorticotropic hormone; GH, growth hormone; JS, Joubert syndrome; MPHD, multiple pituitary hormone deficiency; TSH, thyroid-stimulating hormone.

As a result, a rare syndrome, JS may be associated with MPHD. In patients who are evaluated for endocrinological problems and syndromic signs, association between JS and MPHD should be considered and patients should be evaluated in this respect.

Learning points.

• JS-related disorders (JSRD) are a group of developmental delay, multiple congenital anomaly syndromes whose most descriptive finding on MRI is molar tooth sign (MTS).

• Rarely, Joubert syndrome can be presented with multiple pituitary hormone deficiency (MPHD).

• JSRD should be considered in the differential diagnosis of patients with syndromic findings and MPHD.

• When the MTS is detected on MRI, MPHD should be kept in mind and endocrinological examination should be done.