PITUITARY STALK INTERRUPTION SYNDROME CAUSED BY NOVEL COMPOUND HETEROZYGOUS MUTATIONS IN THE KATNIP GENE

Abstract

Pituitary stalk interruption syndrome (PSIS) is characterized by the coexistence of an absent or thin pituitary stalk, an ectopic posterior pituitary (EPP) lobe, and an absent or hypoplastic anterior pituitary lobe. A 1-year-old boy presented with micropenis, and undescended testis associated with growth hormone, thyroid stimulating hormone, and gonadotropin deficiencies. Pituitary hypoplasia, EPP, and a missing pituitary stalk were seen on magnetic resonance imaging (MRI). Whole-exome sequencing (WES) revealed compound heterozygous variants in the KATNIP gene (NM_0.15202.5: c1461G>A / c.4035delC) in the recruited individual, and subsequent familial segregation showed that family established the trans position for c.1461G>A and c.4035delC variants.

INTRODUCTION

Pituitary stalk interruption syndrome (PSIS) is a rare congenital anomaly of the pituitary gland characterized by the absence or thinness of the pituitary stalk, an ectopic posterior pituitary gland and a hypoplastic or aplastic anterior pituitary gland (1).

According to studies, PSIS patients have variable levels of anterior pituitary hormones such as thyrotropin, gonadotropin, corticotropin, and growth hormone (2, 3). The clinical presentation varies depending on the age of the patient at the time of diagnosis. Clinical presentations in the neonatal period are neonatal hypoglycemia, prolonged neonatal hyperbilirubinemia, micropenis, and cryptorchidism. It manifests as short stature in childhood and adolescence (4).

Katanin interaction protein (KATNIP), whose alternative name is KIAA0556, encodes a microtubule-associated ciliary base protein that appears to regulate microtubule stability and its mutation affects the stabilization of intracellular microtubules, causing in Joubert syndrome, a ciliopathy disease (5).

We presented a rare case of PSIS caused by a new mutation in the KATNIP gene, which resulted in multiple pituitary hormone deficiency without any neurological finding.

CASE REPORT

A 12-month-old male patient was referred to us by pediatric urology for micro penis and undescended testis. He was born with 3250 gr as term birth by spontaneous vaginal delivery, had a history of hospitalization in the neonatal intensive care unit for 2 days due to jaundice. Neurologic development was comparable to peers. In the family history, parents were healthy, there was no consanguinity and the mother’s previous pregnancy was terminated due to an anomaly; parents don’t know what the anomaly was. Anthropometric measurements: his height, weight, and head circumference were 67 cm (SDS: -2.08), 10.2 kg (SDS: 0.65), 45 cm (SDS: -0.37), respectively. In the physical examination, he had frontal bossing, sparse hair, a testicular volume 1/1 ml and a stretched penile length of 1 cm. Other system examinations were regular. Laboratory examinations revealed central hypothyroidism, prolactin deficiency, low IGF-1 and IGFBP3 levels (Table 1). After showing low basal cortisol, ACTH stimulation test was performed with 1 mcg Synacthen^®. Peak cortisol level was 20.3 μg/dl, adrenal insufficiency was excluded. In hCG stimulation test, total testosterone level was 3.28 ng/ml, dihydrotestosterone level was 330.81 pg/ml, which was normal. GH stimulation tests with L-dopa and glucagon revealed low basal GH levels and reduced GH response (peak GH of 0.12 ng/ml and 0.55 ng/ml, respectively). There was no posterior pituitary dysfunction. The patient’s urine volume and density were normal. Pituitary MRI was performed to evaluate the hypothalamic-pituitary and pituitary stalk function. Empty Sella and ectopic neurohypophysis were detected (Fig. 1 A-C).

Table 1.

Patient laboratory examinations

Hormonal Tests	Patient results (Reference Ranges)	Hormonal Tests	Patient results (Reference Ranges)
FT4	11.14 (11.4-19.4 pmol/L)	IGFBP 3	0.673mg/L (SDS: -2.08)
TSH	0.96 (0.88-5.42 uIU/ml)	Total testosterone	<0.13 (0-4.92 ng/ml)
Cortisol	6.8 (0.54-15.9 μg/dl)	Dihydrotestosterone	106.61 (<50 pg/ml)
ACTH	9.8 (<46 pg/ml)	AMH	0.09 (56.6-495 ng/ml)
Prolactin	0.82 (3.9-31.45 ng/ml)	FSH	0.18(1.5-12.4 mIU/ml)
IGF-1	29.7 (0-129 ng/ml SDS 2.42)	LH	0.06 mIU/ml

TSH: Thyroid stimulating hormone, ACTH: Adrenocorticotropic hormone, IGF-1: Insulin-like growth factor 1, IGFBP3: Insulin like growth factor binding protein 3, AMH: Anti Mullerian Hormone, FSH: Follicle stimulating Hormone, LH: Luteinizing Hormone, FT4: free Thyroxine.

Figure 1.

A: Pituitary MRI: Appearance consistent with ectopic neurohypophysis showing slightly hyperintense signal on T1W images anterior to the optic chiasm in the suprasellar area, empty sella. B: Mid Sagittal contrast-enhanced T1 weighted MRI: No pituitary stalk was identified. C: Coronal contrast enhanced T1 weighted MRI showing empty sella and ectopic neurohypophysis.

Genetics study

Whole-exome sequencing (WES) was performed. Data were obtained using the Twist Human Core Exome Plus kit (Twist Bioscience, San Francisco, CA, USA) on the NovaSeq6000 sequencer (Illumina, San Diego, CA, USA) and analyzed using Ingenuity Variant Analysis software (Qiagen, Hilden, Germany). All studies were carried out in accordance with manufacturer’s instructions. Compound heterozygote KATNIP (KIAA0556) mutations were detected.

The first variant is a heterozygous nonsense mutation - KATNIP (NM_0.15202.5): c1461G> A - leads to premature stop codon (pTrp487Ter). It is registered in the dbSNP database with the number rs1488492476 (https://www.ncbi.nlm.nih.gov/snp/rs1488492476#variant_details). Although this mutation was reported as heterozygous in seven individuals in the Gnomad database with 0.000004 frequency (https://gnomad.broadinstitute.org/variant/16-27708776-G-A?dataset=gnomad_r4); there is no record of it in the Clinvar database and classified as likely pathologic in the Varsome platform (https://varsome.com/variant/hg19/rs1488492476?annotation-mode=germline).

The second one is a heterozygote frameshift mutation - KATNIP (NM_0.15202.5):c.4035delC leads to premature stop codon (pIle1346SersTer36), likely pathogenic mutation (https://varsome.com/variant/hg19/NM_015202%20c.4035DELC) and is not reported neither in the population databases nor mentioned in published reports (novel) and classified as likely pathologic in the Varsome platform (https://varsome.com/variant/hg19/NM_015202%20c.4035DELC?).

We performed the segregation analysis in the whole family. The KATNIP gene was amplified and sequenced using the NGS method. The mother was found to be carrier of the c.1461G>A, the father carrier of the mutation c.4035delC (Figs 2, 3). Both parents of the proband are asymptomatic.

Figure 2.

KIAA0556-c.1461G>A-p. Trp487*-rs1488492476- NM_015202.4. Mother– Normal/ Father – Heterozygote.

Figure 3.

KIAA0556-c.4035delC-p. ıle1346fs- NM_015202.4. Mother–Heterozygote/ Father – Normal.

The combination of these variants forms a compound heterozygous condition having a high probability to be the cause of the disease.

Since KATNIP pathogenic mutations were compatible with Joubert syndrome in the genetic databases, the patient was followed up in the pediatric neurology department for neurological involvement. Brain magnetic resonance imaging was requested by the patient to examine Joubert syndrome; it was found to be normal. Renal ultrasound was normal. The treatments were initiated for central hypothyroidism, micropenis and GH deficiency with L-thyroxin, androstanolone and somatropin. At the end of the first and second years of the treatment, heights were 78 cm SDS (-0.79), 98.7 cm SDS (0.07), and growth velocities were 11 cm and 10.7 cm, respectively. After androstanolone treatment, the stretched penile length was 3 cm.

DISCUSSION

Pituitary stem interruption syndrome (PSIS) is a rare anatomical defect of the pituitary gland (1). PSIS occur at a rate of 0.5 per 100,000 live births (6). According to different studies, the male to female ratio varies between 2.3-6.9/1 (3, 7) The average age is uncertain because studies have reported it in a variety of ways: 9.6 years (3) and 19.7 years (7). The exact physiology of this syndrome is not fully understood. One of the hypotheses considered in the etiology is the "traumatic hypothesis" which suggests that ectopic posterior pituitary is caused by hypertrophy and reorganization of proximal axons as a result of traumatic birth, especially breech presentation (8). Another theory is that decreased hormone release caused by anterior lobe hypoplasia and failure leads to an increase in the frequency of breech presentation (10).

Depending on the age range, clinical findings vary. Hypoglycemia, prolonged jaundice, undescended testicles and micropenis in the neonatal period, short stature, and delayed puberty in childhood are such characteristic symptoms (1). Our patient was referred to us with a micropenis and undescended testis. By the early detection of the initial signs an early diagnosis was made achievable.

In individuals with PSIS, anterior pituitary hormones such as growth hormone, gonadotropin, corticotropin, and thyrotropin are affected at different levels. In a study by Guo et al. involving 55 individuals, the prevalence of growth hormone, gonadotropin, corticotropin, and thyrotropin deficiency was observed to be 100%, 95.8%, 81.8%, and 76.3%, respectively (7). In the Han et al. study, 102 (89.4%) of the 114 PSIS individuals were men. Ninety-one patients (91.9%) had a history of breech births. In 89 cases (71.8%), short stature was found. Growth hormone, gonadotropin, corticotropin, and thyrotropin deficits were all present in 100.0%, 94.0%, 84.2%, and 74.6% of people, respectively (10).

Another issue reported in PSIS patients was the development of irregularities in prolactin levels. In a Chinese cohort, 36.2% of patients had hyperprolactinemia, whereas 1.7% had hypoprolactinemia (11), and in another study, hyperprolactinemia was detected in 28.1% of the patients (10). Meanwhile, Raynaud et al. found hypoprolactinemia in 14.5% of cases and hyperprolactinemia in 16.9% of cases (3). Elevated prolactin levels are thought to be caused by an interruption of dopaminergic inhibition (12). In our case, hypoprolactinemia was detected.

Genetic analysis is required in patients diagnosed with PSIS. According to recent publications, this should be considered as the phenotypic spectrum of a genetic condition. Numerous genes in the hypothalamic-pituitary development-related Wnt, Notch, and Shh signaling pathways, including PIT1, PROP1, LHX3/LHX4, PROKR2, OTX2, and HESX1, have been discovered to be associated to PSIS (3,11). Brauner et al. examined 39 children with PSIS from 37 families in one study, and Joubert syndrome was found in 5 patients (13). One of the patients carried combined heterozygous variants in the KIAA0556 gene (13); whereas previously, there were homozygous variants in KIAA0556 that have been reported in association with micropenis, pituitary hypoplasia, pituitary stalk anomalies, cleft palate, and cerebellar hypoplasia in Joubert syndrome 26 (14). Fang et al. reported that mutations in the PTCH2, HHAT, MAPK3, EGR4, SPG11, GLI2, and CDON genes may be associated with PSIS. Additionally, Fang et al. showed that 14 of 59 mutated genes are involved in the Hedgehog signaling pathway (GLI1, GLI2, PTCH1, PTCH2, CDON, CREBBP, KIF7, LHX4, HHAT, STK36, MAPK3, SMO, PRKAR2A and PRKAR2B) and reported that genetic defects in the Hedgehog signaling pathway can result in PSIS (15). On the other hand, Zwaveling-Soonawala et al. reported that alterations were found in many genes related to midline brain development in patients with PSIS, and they hypothesized that PSIS might result from polygenic disorders (16). Wang et al. proposed a new hypothesis and reported that the clinical diversity observed in PSIS patients may be due to a combination of genetic background, specific mutations, and variable degrees of traction at birth (17). However, since there was no information about traction during labor in our case and we had only one case, we did not have sufficient data to support this possible hypothesis of Wang et al.

A conserved basal body and Microtubule (MT)-associated protein called KIAA0556 interacts genetically with ARL13B (JBTS8) and forms biochemical associations with several ciliary proteins. Additionally, KIAA0556 affects the integrity of the MT network, perhaps by directly regulating the MT severing proteins of katanin (5). Through these effects, KIAA0556 maintains ciliary integrity and thereby supports Sonic Hedgehog and Wnt signaling, which are critical for hypothalamo–pituitary development (16). Pathogenic mutations in this gene are a known cause of Joubert syndrome type 26 (5), which is typically characterized by the “molar tooth sign” and broader ciliopathy features. However, the phenotypic spectrum extends beyond that of classical Joubert syndrome. Our patient carried compound heterozygous KIAA0556 variants and a PSIS phenotype, but neurological examination and brain MRI were normal. In line with these genetic findings, Sanders et al. described siblings with JBTS26 and panhypopituitarism (5). Taken together, these observations highlight the phenotypic variability of KIAA0556 mutations and suggest that their clinical impact may extend beyond the classical features of Joubert syndrome.

Joubert syndrome (JS), neuro ectopic pituitary, and hypothalamic insufficiency have been related in cases that have been published in the literature. Disorders associated with Joubert syndrome (JSRD) can manifest in a range of ways clinically, including neurological symptoms and various organ involvement (hepatic fibrosis, polydactyly, coloboma of the eye, retinal dystrophy, cystic dysplasia of the kidney, etc.). It has been demonstrated that JS and mutations in more than 35 genes are related. Hypotonia, developmental delay or mental retardation, oculomotor apraxia and respiratory problems are the hallmarks of classical JS (19). In our case, neurological findings were entirely normal. Our patient did not show any Joubert syndrome features. Our patient’s brain and cerebellar MRI also were normal. No neurological function was affected.

In comparison to patients with an isolated growth hormone deficiency, PSIS cases that were discovered at an early stage responded better to growth hormone therapy (20). Our case was diagnosed at the age of 12 months, and we assume successful performance from the early onset of growth hormone in the long-term.

In conclusion, KATNIP (KIAA0556) gene which is associated with Joubert Syndrome type 26 in the genetic database (https://www.omim.org/entry/616650) should be considered in the PSIS genetic test panel.

“This case was previously presented as a poster at the 60^th Annual Meeting of the European Society for Pediatric Endocrinology (ESPE 2022), Rome, Italy, 15–17 September 2022 (Semra Bahar).”

Conflict of Interest

The authors declare that they have no conflict of interest.