American Journal of Medical Genetics 37511-515 (1990)

Persistent Hyperinsulinemic Hypoglycemia of Infancy (“Nesidioblastosis”):Autosomal Recessive Inheritance in 7 Pedigrees Benjamin Glaser, Moshe Phillip, Rivka Carmi, Ester Lieberman, and Heddy Landau Departments of Endocrinology and Metabolism (B.G.1 and Pediatrics (H.L.), Hadassah Medical Center, E i n Kerem, Jerusalem, and Pediatric Endocrine Unit (M.P.,E.L.) and Clinical Genetic Unit (R.C.), Division of Pediatrics, Soroka University Hospital, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.

Persistent Hyperinsulinemic Hypoglycemia of Infancy (PHHI) is a rare disease characterized clinically by persistent hypoglycemia with inappropriately elevated circulating insulin concentrations. Here we report on 7 pedigrees including 21 cases. The pedigrees are derived from 3 distinct ethnic groups, and include a very large Bedouin family, and Arab family, and 5 smaller pedigrees of Jewish families all of Eastern European origin. Data obtained from these families and from other families reported in the literature strongly suggest that PHHI is inherited as an autosoma1 recessive disorder.

KEY WORDS: hypoglycemia, hyperinsulinism, autosomal recessive, consanguinity INTRODUCTION Persistent Hyperinsulinemic Hypoglycemia of Infancy (PHHI) is a rare disease characterized clinically by persistent hypoglycemia with inappropriately elevated circulating insulin concentrations [Stanley and Baker, 1976; Marks, 1981; Aynsley-Green et al., 1981; Landau et al., 19821. As its name implies, this disease is most frequently diagnosed in the newborn or infant, although a number of cases have been reported in adults as well [Harness et al., 19811.Previously called “nesidioblastosis,” this name has fallen into disuse due to a controversy regarding the significance of the pancreatic histology LJaffe et al., 1980; Goossens et al., 1989; Ariel et al., 19881. Most cases reported in the literature are sporadic; however, a number of familial cases of PHHI have been documented [Matthew et al., 1988; Schwartz Received for publication July 28, 1989; revision received March 14, 1990. Address reprint requests to R. Carmi, M.D., Clinical Genetic Unit, Soroka Medical Center, P.O. Box 151, Beer-Sheva 84101, Israel.

0 1990 Wiley-Liss, Inc.

1979; Woo et al., 1976; Falkmer et al., 1981; Becker, 1978; Hammersen, 1980; Rose, 19861. Nevertheless, pedigrees large enough to confirm the mode of inheritance are rare. Here we report on 7 pedigrees, which include 21 confirmed PHHI cases, from 3 different ethnic groups, 2 of which are known for their high rate of consanguinity.

RESULTS Patients The clinical details of our 21 patients are shown in Table I. Patients 7-14 and 17 were previously reported as shown in Table I. The diagnosis of PHHI was based on established criteria [Aynsley-Green et al., 1981; Stanley and Baker, 1976; Landau et al., 19821. Hypoglycemia with inappropriately high insulin levels was documented in 18 out of 21 patients as shown in Table I. In 2 patients (G-11-1 and 2) this was adequately documented at Boston Children’s Hospital, but the exact data are not available to us a t this time. The one remaining patient (A-VII-02)was investigated and treated in another hospital in Israel where a definitive diagnosis was made, but here too, the data is not available to us. Other causes of neonatal hypoglycemia including hormonal deficiencies (GH, cortisol, thyroid) and metabolic disorders were excluded in all patients. Glucose requirement to maintain euglycemia was >12 mgikgimin (median 19.4, range 12-27 mgikgimin) in all patients where this data is available. Sixteen patients had onset of disease within the first 3 days of life, one a t age 2 weeks, and 3 a t the age of 3-4 months. In one patient the age a t diagnosis is unknown. Of the 16 patients with severe disease, 14 underwent sub-total pancreatectomy, one died of sepsis before surgery, and one is treated with the long-acting somatostatin analogue octreotide LGlaser et al., 19891. The 4 patients with milder disease responded well to diazoxide treatment (10-15 mgikgiday), but one of these required a feeding gastrostomy. Pathological examination of 14 patients showed diffuse distribution of p-cells incorporated in the ductular wall, in small clusters, and in the islets of Langerhans. A detailed description of the pathologic findings of 5 of

512

Glaser et al. TABLE I. Patient - Data

Pt. No.

Pedigree code ~~

1 2 3 4 5 6 7 8 9 10 11 12 13 14

A-VI-04 A-VI-05 A-VI-07 A-VI-10 A-VI-17 A-VII-02 A-VII-03 B-VI-05 B-VII-11 B-VII-12

15 16 17 18 19 20 21

Age of onset” 4m 6h 7h 3d “Few h ’

-

~

Birth wt (kg) 3.8 3.4 4.13 3.8 3 -

~~

Glucose (mgidl) 14 20 28 14 27 c

Insulin (r*.Uiml) -~ 26 16 52 18 15 c

c-v-3 D-111-4 D-111-7

c-v-1

2w 2h 2d Id Id 12h 20h 2h

2.4 4.5 3.6 3.8 4.35 4.06 3.5 5.27

30 25 1.2 3.6 26 1.2 22 26.6

E-11-3 E-11-4 F-11-2 F-11-4 G-11-1 G-11-2 G-11-3

2h 4m 3h 2h 3m lh 2h

4.4 3.8 3.1 4.98 4.75 4.66 4.36

21 27 26 25

29 7.7 27 23

32

14.5

e

13 98.8 21 113 16 25 8.5 11.6

Severity of disease

Pathologyb

Mild Severe Severe Severe Severe Unknown Severe Severe Severe Severe Severe Severe Mild Severe

None None (died) Diffuse Diffuse Focal Unknown Diffuse Diffuse Diffuse Diffuse Diffuse None Diffuse (Bx) Diffuse

Severe Mild Severe Severe Severe Severe Mild

Diffuse None Diffuse Diffuse Diffuse Diffuse None

Previously reported in

Glaser e t al. [19891 Glaser and Landau [19901 Glaset et al. [1989] Glaser et al. [19891 Landau et al. [1982] Glaser and Landau [1990] Landau et al. [1982] Landau et al. [1982], Hirsh et al. 119771 Landau et al. [1982]

~~

“Age at first recognition of symptoms. h = hours; d = days; w = weeks; m = months. bPancreatic histology. See text for detailed description. ‘These patients were diagnosed and treated a t other hospitals so specific data is not available. Patients 19 and 20 were treated a t the Boston Children’s Hospital.

these patients is reported by Ariel et al. [1988]. Focal “nesidioblastosis,” characterized by nodular hyperplasia of poorly circumscribed islet-like cell clusters including ductuloinsular complexes [Goosens et al., 19891, was found in one patient [A-VI-171.

Pedigrees Figure 1 represents the pedigree of a large Bedouin family [Pedigree A] with 7 affected children in 5 nuclear

families where all the parents of affected children are first cousins. The marked consanguinity typical of the Bedouin population is evident. Five of the patients had severe disease, one had mild disease, and in one the severity of the disease is not known. Diffuse involvement of the pancreas was found in 3 pathologic specimens and focal involvement was found in one, Pedigree B shown in Figure 2 depicts a large Arab family with 3 documented cases of PHHI. It consists of 2

I

II 111

IV

V

VI VI I

/

Fig. 1. Pedigree of large Bedouin family demonstrating 7 cases of PHHI in 5 nuclear families. All parents of affected cases are first cousins.

PHHI-An Pedigree B

Autosomal Recessive Disease

513

Pedigree C I

I

1 I1

Ill

Ill

IV I' V

IV

V

1 2

VI VI I

3

Pedigree D 1

2

3

4

5

6

7

8 9 10 11 1 2

Fig. 2. Pedigree of large Arab family showing 3 cases of PHHI in 2 nuclear families. The parents of patient VI-5 were described as being first cousins, but exact details of their relationship is not known (see text).

o, ,z*o Ill :I

I 2 3 4 5 6 7 8 9 1 0 Pedigree E I

%

*

nuclear families where both sets of parents are first II cousins, and the 2 families are interlinked by a complex 1 2 3 4 5 mesh of intermarriage. The parents of patient B-VI-5 Pedigree F were described a s first cousins in the initial admission I history, but were not available at the time ofthis writing to describe exactly how they are related. This pedigree is II largely based on information obtained from the parents 1 2 3 4 5 6 ofpatients B-VII-11 and -12. Infants B-VI-1, B-VI-3, and B-VII-10 died at home within the first few days of life, Pedigree G B-VII-10 being described as plethoric and large for gesI tational age (LGA). Therefore it is likely that these 3 infants also suffered from PHHI. II The remaining 5 pedigrees shown in Figure 3 are all of 1 2 3 Ashkenazi Jewish extraction. All parents except one Fig. 3. Five pedigrees of Ashkenazi Jewish families showing 11 [mother in Pedigree El are of Eastern European origin. cases in 7 nuclear families. Despite attempts to do so, no information suggesting any connection between these 5 pedigrees could be obtained. Furthermore, the parents of the affected sibs denied any interrelationship beyond that which is value between 0.8 and 0.7 for which the autosomal recessive hypothesis is highly acceptable. shown here (Pedigrees C and D). Parents of all PHHI patients are healthy except for DISCUSSION one where gestational diabetes was diagnosed during the sixth pregnancy-7 years after the birth of the last These studies confirm and expand upon previous reaffected child [F-II-4].The maternal grandfather in ped- ports of familial occurrence of PHHI. Two of the 3 ethnic igree F and the paternal grandfather in pedigree E had groups represented in our pedigrees are known for havType 2 (non-insulin-dependent) diabetes. All affected ing a relatively large degree of consanguinity, and in our children were the products of normal uncomplicated 2 largest pedigrees the parents of all affected cases are pregnancy, labor, and delivery. No additional endocrine first cousins. Of the other familial cases reported in the abnormalities were found in these families with the literature, one is a Greek Cypriot family [Woo et al., exception of non-insulin-dependent diabetes in ped- 19761, one is Arab [Mathew et al., 19881, and one is igrees D and F. Black American [Schwartz et al., 19791. The remaining Using the proband method for testing the hypothesis reports do not state ethnic origin. Both sexes are affected of autosomal recessive inheritance in these families, we equally, and with the exception of one family [Rose et al., observed 14 affected individuals out of a total of 56 sibs 19861none of the parents of any reported affected cases (the 4 deceased newborns and one fetal demise in ped- had any evidence of hypoglycemic disorders. In the famigree B were not counted), which is exactly the expected ily described by Rose et al. [1986] both parents had 25%. Application of the direct a priori method for the symptomatic episodes of hypoglycemia but spontaneous same purpose (Table 11)produced an expected number of hyperinsulinemic hypoglycemia was not documented in approximately 22 affected individuals, while 21 were either. The assumption that both parents carried a domactually observed. Chi square was 0.069, giving a P inant gene seems unjustified for such a n uncommon

514

Glaser et al.

TABLE 11. Direct A-Priori Method for testing the Autosomal Recessive Hypothesis“ No. of Sibs No. of per family _ _ - -families -1 2 2 3 3 2 4 1 5 2 6 3 7 8 1 9 1

No. of ~~~

Total

affected -

No. of non-

Total No.

affected

of sibs 2 6

- - -

~~

2 3 4 2 3 5

-

1 1 21

-

3 2 2 7 13 7 8 42

6 4 10 18 8 9 63

qtr

1.0 0.5714 0.4324 0.3657 0.3278 0.3041 0.3885 0.2778 0.2703

-

Esp. 3.428 2.592 2.628 3.278 5.474

-

2.222 2.433 22.055

“ ~ ~ ~ 0 . 0( / I6 1 9 d.f. . 0.8>P>0.7

disease. A manifesting heterozygous state might be a better explanation; however, no other similar situations have been described. Our data and that of the literature strongly suggest a n autosomal recessive mode of inheritance for this disease, a suggestion which is supported by statistical tests described here. Pedigree D presents a n unusual pattern for segregation of a n autosomal recessive gene. However, an assumption of a dominant gene in this case demands that both fathers are carriers of a non-penetrating gene. It seems more likely that both mothers who come from the same ethnic background are carriers for this gene which may be more frequent than previously suspected among Jews of Eastern European origin. There is no definite preponderance of either Type 1 (insulin dependent) or Type 2 (non-insulin dependent) diabetes in our families. The finding of Type 2 diabetes in 2 of our Jewish pedigrees is not inconsistent with the high prevalence of this disease in this population. Unlike Type 1 diabetes, there does not appear to be any linkage to HLA markers [unpublished observations]. The specific defect in the various ethnic groups may be different, but there is no clinical evidence to suggest that patients from different pedigrees have different clinical presentations or courses. All but one of our patients where pathologic material was available for examination showed a diffuse pattern of immature islets which is difficult to distinguish on histologic grounds from normal newborn pancreas [Goossens et al., 1989; Jaffe et al., 19801. The one patient with focal islet cell proliferation appeared in a pedigree where the remaining patients had diffuse lesions suggesting that these 2 apparently different histologic appearances may be different manifestations of the same basic defect. The relative incidence of familial vs. sporadic PHHI is not known. Our PHHI patient population consists of 2 1 familial cases and 20 apparently sporadic cases. Of the sporadic cases, however, 13 come from the same ethnic backgrounds as the familial cases. In the world literature, the relative incidence of sporadic cases appear to be much greater than that of familial cases. This may represent problems of ascertainment, small nuclear families, or genetic heterogeneity in different ethnic groups. There was no clinical difference between the familial

and the sporadic cases in our series, with most of the cases having severe disease, and only a few being manageable without surgery. Some previous studies report a higher incidence of milder cases suggesting the possibility of different pathophysiology in different population groups [Labrune et al., 19891. The metabolic defect in this disease is not known, but clearly the disease is neither neoplastic nor progressive. This is distinctly different from the pattern seen in Multiple Endocrine Neoplasia Q p e 1 (MEN 1)where a similar histologic picture of “nesidioblastosis” has been reported [Bloodworth and Elliot, 1963; Vance et al., 19721.MEN 1usually presents in early adulthood and is characterized by hyperparathyroidism, pituitary tumors, and pancreatic endocrine tumors which are frequently malignant and only rarely associated with hypoglycemia. The gene responsible for the MEN 1syndrome is located on chromosome 11and appears to be a mutant of the wild-type gene which regulates the normal differentiation of the affected endocrine cells. MEN 1 tumors are associated with somatic deletion of the normal allelle and unmasking of the recessive mutation [Larsson et al., 19881. The mode of inheritance of MEN 1,therefore, is autosomal dominant with variable penetrance. In vivo studies of p-cells obtained from PHHI patients who underwent therapeutic pancreatectomy have demonstrated a functional abnormality characterized by constant levels of insulin secretion in the presence of glucose concentrations ranging from 0 to 16.7 mmol. Similarly, there is a lack of sensitivity to non-glucose nutrient stimuli, but preserved responsiveness to CAMP stimulation and suppression with somatostatin and epinephrine [Kaiser et al., 19901. This suggests that the defect in this disease may be in the mechanism by which the p-cell recognizes glucose and regulates insulin secretion. Further work is needed to locate and identify the gene responsible for this rare but devastating disease. In addition to its obvious importance of facilitating genetic counseling and the pre-natal diagnosis of affected cases, identification of the genetic defect in these patients may have important ramifications for our understanding of the control of insulin secretion.

PHHI-An Autosomal Recessive Disease

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