Japanese 17q12 Deletion Syndrome with Complex Clinical Manifestations

Abstract

17q12 deletion syndrome is a rare chromosomal anomaly with variable phenotypes, caused by the heterozygous deletion of chromosome 17q12. We herein report a 35-year-old Japanese patient with chromosomal 17q12 deletion syndrome identified by de novo deletion of the 1.46 Mb segment at the 17q12 band by genetic analyses. He exhibited a wide range of phenotypes, such as maturity-onset diabetes of the young (MODY) type 5, structural or functional abnormalities of the kidney, liver, and pancreas; facial dysmorphic features, electrolyte disorders; keratoconus, and acquired perforating dermatosis. This case report provides valuable resources concerning the clinical spectrum of rare 17q12 deletion syndrome.

Introduction

Human chromosomal deletions, commonly diagnosed as copy number variations (CNVs) from the normal number of genomic copies, disrupt the function of located genes and result in the onset of related diseases with complex phenotypes (1,2).

Chromosome 17q12 deletion syndrome (OMIM: 614527), also known as 17q12 recurrent deletion syndrome (NCBI: GeneReviews^Ⓡ) or 17q12 microdeletion syndrome, is rare and associated with various clinical phenotypes (3-6). Recurrent aberrations in chromosomal 17q12, the segment of which is subjected to non-allelic homologous recombinations, resulted in 17q12 deletions or duplications (7,8). Previous literature regarding 17q12 deletion syndrome emphasized that the most common (50%) characteristics are structural or functional kidney defects, neurodevelopmental/neuropsychiatric disorders, mild dysmorphic features, and hyperparathyroidism (6). Among the deleted genes on chromosome 17q12, hepatocyte nuclear factor 1β (HNF1B) has been associated with maturity-onset diabetes of the young (MODY) type 5, characterized by pancreatic atrophy, renal cystic disease, hepatic abnormalities, hypomagnesemia, and hyperuricemia (9-13). Due to the rarity of 17q12 deletion syndrome, the clinical characteristics of this syndrome and its diagnostic evaluation are still undefined.

We experienced a Japanese case of 17q12 deletion syndrome identified by the de novo deletion of the 1.46 Mb segment at the 17q12 band, including the HNF1B gene. We herein report the clinical spectrum and discuss the possible roles of the responsible genes in our patient.

Case Report

A 35-year-old Japanese man was admitted to our department for hyperglycemia, headache, fatigue, and dizziness with symptom of orthostatic hypotension. According to the patient's medical history, he had been diagnosed with congenital hydronephrosis at six years old. The patient had depression and mild intellectual disability. The right kidney was dissected after an external abdominal injury. At 27 years old, he was diagnosed with bilateral keratoconus (Fig. 1A-C) and underwent a corneal transplant in the left eye. At this time, the patient was also diagnosed with diabetes mellitus without autoimmune antibodies and started insulin therapy. He was treated on an outpatient basis with poorly controlled diabetes mellitus, and occasionally suffered from diabetic ketosis due to the omission of treatment. Both his parents and father's relatives had diabetes mellitus (Fig. 1D).

Figure 1.

Clinical features of the patient with keratoconus, diabetes mellitus, dysmorphic features, and abnormalities of the urinary tract. (A) Anterior segment optical coherence tomography (AS-OCT) shows a protruding cone-shaped cornea. (B) In corneal topography, Placido rings appear as horizontally elongated elliptical shapes. (C) Slit lamp photograph showing corneal opacity caused by acute corneal hydrops in keratoconus. (D) Pedigree of a Japanese family with diabetes mellitus. Individuals with diabetes mellitus are noted by filled symbols. The proband is indicated with an arrow. (E) Image of the proband presented dysmorphic facial features with low body weight. Abdominal CT revealed the agenesis of the body and tail of the pancreas (F), solitary hydronephrotic kidney with small cysts (G), and enlargement of the scrotum (H). OHA: oral hypoglycemic agents

Upon physical examination, the patient's height and weight were 165.5 cm and 46.8 kg, respectively. The body mass index (BMI) was 17.1 kg/m². The patient presented with facial dysmorphic features, such as down-slanted palpebral fissures, deep-set eyes, long and narrow face, small chin, and high forehead with hair loss (Fig. 1E). In addition, acquired perforating dermatosis was observed on the skin around the neck, clavicle, and extremities (Fig. 1E). Although brain computed tomography (CT) scan revealed no apparent findings, the abdominal CT scan displayed the atrophy of the pancreas, hydronephrosis of the left solitary kidney with multiple small cysts, and enlargement of the scrotum (Fig. 1F-H).

As shown in Table 1, laboratory tests showed that the plasma glucose level was 241 mg/dL, and the hemoglobin A1c (HbA1c) level was 17.1% (normal reference value: 4.9-6.0%). Both glutamic acid decarboxylase (GAD) and insulinoma-associated protein-2 (IA-2) antibodies in the serum were negative. The fasting C-peptide level was 0.04 ng/mL, indicating the loss of insulin secretory capacity. Intensive insulin therapy (insulin degludec 9 units/day and rapid-acting insulin 23 units/day) was required upon hospital discharge. The values of aminotransferases were elevated without a specific cause. Serum levels of creatinine and blood urea nitrogen were 1.52 mg/dL and 15.0 mg/dL, respectively. Furthermore, the patient had chronic electrolyte abnormality of hypokalemia with potassium supplementation. The serum level of magnesium was 0.9 mg/dL, and the fractional excretion of magnesium (FE Mg) was 29.8%, indicating excessive urinary magnesium excretion (14). Pituitary, adrenal, thyroid, and parathyroid functions were normal.

Table 1.

Summary of Laboratory Data.

		Component		Result		Reference range
Biochemistry		TP (g/dL)		6.9		6.6-8.1
		Alb (g/dL)		4.1		4.1-5.1
		Na+ (mEq/L)		144		138-145
		K+ (mEq/L)		3.0		3.6-4.8
		Cl- (mEq/L)		101		101-108
		Ca2+ (mg/dL)		8.6		8.8-10.1
		Pi2- (mg/dL)		3.7		2.7-4.6
		Mg2+ (mg/dL)		0.5		1.8-2.3
		AST (U/L)		77		13-30
		ALT (U/L)		116		10-42
		LDH (U/L)		264		124-222
		ALP (U/L)		341		38-113
		γGTP (U/L)		251		13-64
		ChE (U/L)		221		240-486
		T-Bil (mg/dL)		0.2		0.4-1.5
		AMY (U/L)		80		44-132
		CK (U/L)		32		59-248
		Intact-PTH (pg/mL)		48.4		10.3-65.9
		BUN (mg/dL)		15.0		8-20
		CRE (mg/dL)		1.52		0.65-1.07
		UA (mg/dL)		8.1		3.7-7.8
		T-cho (mg/dL)		171		142-248
		TG (mg/dL)		118		40-234
		Glucose (mg/dL)		167		73-109
		HbA1c (%)		18.3		4.9-6.0
		Insulin (μU/mL)		3.2		<18.7
		C-peptide (ng/mL)		0.04		0.5-2.0
		Anti-GAD (U/mL)		<5.0		<5.0
		Anti-IA-2 (U/mL)		<0.6		0-0.6
Blood count		WBC (×103/mL)		7.12		3.3-8.6
		RBC (×106/mL)		3.77		4.35-5.55
		Hb (g/dL)		11.4		13.7-16.8
		Ht (%)		33.5		40.7-50.1
		MCV (fL)		89.0		83.6-98.2
		MCH (pg)		30.1		27.5-33.2
		MCHC (%)		33.9		31.7-35.3
		PLT (×103/mL)		318		158-348
Urine		Protein		2+
		Glucose		-
		RBC		-
		Ketone		-

TP: total protein, Alb: albumin, AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, γGTP: gamma-glutamyl transpeptidase, ChE: cholinesterase, T-Bil: total bilirubin, AMY: amylase, CK: creatine kinase, PTH: parathyroid hormone, BUN: blood urea nitrogen, Cre: creatinine, UA: uric acid, T-cho: total cholesterol, TG: triglyceride, GAD: glutamic acid decarboxylase, IA-2: insulinoma-associated protein-2, WBC: white blood cells, RBC: red blood cells, Hb: hemoglobin, Ht: hematocrit, MCV: mean corpuscular volume, MCH: mean corpuscular hemoglobin, MCHC: mean corpuscular hemoglobin concentration, PLT: platelets

These clinical characteristics led us to suspect a mutation or deletion of HNF1B gene. Indeed, the HNF1B score, which was developed as a screening tool for rational genetic testing (15), was 18 points (Table 2); a score of more than 8 points was indicative of HNF1B mutations (sensitivity 98.1%, specificity 41.1%) (15). After obtaining written informed consent from the patient and both his parents, genetic analyses were performed. In the whole exome sequencing analysis, there were no pathological variants in MODY1-14 genes. However, a multiplex ligation-dependent probe amplification (MLPA) analysis of the MODY1-3, 5 genes (HNF1A, GCK, HNF1B, and HNF4A) revealed a heterozygous deletion of exons 1-9 of the HNF1B gene (Fig. 2A). Based on these findings, we confirmed the diagnosis of HNF1B-MODY (MODY5).

Table 2.

The HNF1B Scores of the Patient.

Characteristics	Item	Value	This patient
Family history		+2
Antenatal renal abnormalities	Uni/bilateral abnormality by renal echography	+2
Kidneys and urinary tract
Lef kidney	Hyperechogenicity	+4
	Renal cysts	+4	4
	Hypoplasia	+2	2
	Multicystic and dysplastic kidney	+2
	Urinary tract malformation	+1
	Solitary kidney	+1	1
Right kidney	Hyperechogenicity	+4
	Renal cysts	+4
	Hypoplasia	+2
	Multicystic and dysplastic kidney	+2
	Urinary tract malformation	+1
	Solitary kidney	+1
Electrolyte or uric acid disorders	Low serum Mg2+ (<0.7 mmol/L)	+2	2
	Low serum K+ (<3.5 mmol/L)	+1	1
	Early-onset gout (>30 years of age)	+2	2
Pathological findings	Oligomeganephronia or glomerular cysts	+1
Pancreas	MODY or hypoplasia of tail and neck of the pancreas and pancreatic exocrine insufficiency	+4	4
Genital tract	Genital tract abnormality	+4
Liver	Liver test abnormalities of unknown origin	+2	2
HNF1B score			18 (>8)

Figure 2.

The diagnosis of 17q12 microdeletion syndrome by a genomic DNA analysis. (A) The copy number variation (CNV) of the MODY genes on a multiple ligation-dependent probe amplification (MLPA) analysis. Large genomic rearrangements of GCK, HNF1A, HNF4A, and HNF1B were examined by Salsa Multiplex (SALSA MLPA Probemix P241-E1 MODY Mix 1 and P357 MODY Mix 2, MRC Holland, Amsterdam, Netherlands). The CNV ratio of the HNF1B gene showed half of the reference value. (B) Karyoview from CytoScan HD at chromosome 17 (left). The red square corresponds to the loss of heterozygosity (right).

Because of the characteristic phenotypes, such as MODY5 and the dysmorphic facial features, we suspected 17q12 recurrent deletion syndrome which is caused by heterozygous deletion of genes at chromosome 17q12, including the HNF1B gene. To further analyze the gene expression profiles, we performed microarray testing using the CytoScan HD array (Thermo Fisher Scientific, Waltham, USA). Molecular karyotyping revealed the comparable deletion in chromosome 17q12 (Fig. 2B). This deletion range was distributed at 1.46 Mb, including genes such as ZNHIT3, MYO19, PIGW, GGNBP2, DHRS11, MRM1, LHX1-DT, LHX1, AATF, MIR2909, ACACA, SNORA90, C17ORF78, TADA2A, DUSP14, SYNRG, DDX52, MIR378J, HNF1B, and YWHAEP7. As neither of his parents had the same deletion mutant, we diagnosed the patient with a de novo deletion mutation.

Discussion

Herein, we report a case of 17q12 deletion syndrome in a patient who exhibited adult-onset diabetes with multiple clinical phenotypes. A wide variety of clinical features, including structural or functional abnormalities of the kidneys and pancreas and neurodevelopmental or neuropsychiatric disorders, have been reported in patients with 17q12 deletion syndrome (16,17). Our patient showed facial dysmorphic changes, renal and genital malformations, liver dysfunction of unknown origin, mild intellectual disability, hypomagnesemia, and hyperuricemia, which are suspected to have been due to the heterogeneous deletion of the 17q12 chromosome. In addition, the patient underwent corneal transplantation for keratoconus, which has not been previously reported. The patient also suffered from orthostatic hypotension, which delayed his hospital discharge.

Many abnormalities and disorders have been attributed to the involvement of HNF1B, a major transcription factor encoded within the chromosome 17q12 region (18). HNF1B plays important tissue-specific roles in the embryonic development of several organs, such as the pancreas, kidney, intestine, liver, and genital tract. The heterozygous mutation of HNF1B gene can cause abnormalities in the above organs (19).

As well as intragenic HNF1B mutations, diabetes mellitus represents a frequent common feature of HNF1B haploinsufficiency based on 17q12 deletion syndrome. A previous case report found that 52% of patients with 17q12 deletion exhibited structural malformations in the pancreas, and 63% had diabetes mellitus (10). In addition, compared with patients with intragenic HNF1B mutations, those with 17q12 deletion have a lower BMI and more frequently require insulin treatment for diabetes (11). Furthermore, three facial dysmorphic features, such as a high forehead, deep-set eyes, and chubby cheeks, were statistically associated with a 17q12 deletion rather than an intragenic HNF1B mutation (5).

The patient had a low level of serum magnesium and a high level of urinary magnesium excretion. Therefore, the patient had been suspected and followed up as Gitelman syndrome. Gitelman-like phenotypes, such as hypomagnesemia, hypokalemia, and hypocalciuria, have been reported to be associated with HNF1B transcription (20). HNF1B regulates the transcription of the FXYD domain-containing ion transport regulator 2 (FXYD2) gene that encodes sodium-potassium adenosine triphosphatase (ATPase) in the distal convoluted tubule, which functions in magnesium reabsorption (21). In the treatment of hypomagnesemia, organic magnesium supplements, such as magnesium aspartate, may be a promising way to reduce hypomagnesemia-related symptoms (22,23). In addition, hypomagnesemia and hyperparathyroidism may increase cardiovascular risk (24). Thus, not only the levels of glucose control, electrolytes, and uric acid but also the cardiac function need to be examined in outpatient care.

We encountered two unique phenotypes in our proband: keratoconus and acquired perforating dermatosis. These two phenotypes have not been previously reported in cases of 17q12 deletion syndrome, and it is unclear whether they are a direct effect of the deleted 19 genes other than HNF1B gene on chromosomal 17q12. Keratoconus may be due to the dysfunction of HNF1B. A recent multi-ethnic genome-wide association study implicated the association of FAM76B and PKHD1 genes with keratoconus (25), and these genes are possible transcriptional targets of HNF1B (GEO accession; GSE119930). In contrast, the etiology and pathogenesis of acquired perforating dermatosis remain unclear (26,27). The acquired perforating dermatosis observed in our proband may have been secondary to the associated metabolic disorders, including diabetes mellitus, chronic renal failure, and hyperuricemia. As 17q12 deletion syndrome exhibits variable penetrance or expressivity due to the haploinsufficiency of responsible genes, further case reports or functional investigation of the genes at the 17q12 deletion region would uncover the atypical features.

In summary, we report a Japanese case of a de novo 17q12 deletion syndrome. Our case comprises variable phenotypes, such as MODY5, structural or functional abnormalities of the kidney and pancreas, facial dysmorphic features, and electrolyte disorders. Our case report may provide valuable resources to expand the spectrum of 17q12 deletion syndrome.

The authors state that they have no Conflict of Interest (COI).

Financial Support

This work was supported by grants from the Japan Diabetes Foundation and Costco Wholesale Japan (Y.H. and Y.H.).