A male newborn was delivered at term of the first uneventful pregnancy, by spontaneous vaginal delivery. Parents were healthy and consanguineous (grandparents first cousins), coming from a small town in the center of Sicily. Anthropometric measures at birth were: weight 4170 g
(98th centile), length 55 cm (> 99th centile), head circumference 35.8 cm (86th centile). Apgar score was 10/10. He was exclusively breastfed, and postnatal clinical course was uneventful. Jaundice due to increased indirect bilirubin levels appeared on the third day of life, and requested phototherapy for 5 days. On the eighth day of life, progressive feeding difficulties, poor sucking, hyporeactivity and lethargy, tachycardia and profuse sweating were suddenly observed. He was transferred to the neonatal intensive care unit (NICU), where a severe salt loss syndrome with hyponatremia and hypochloremia (117 and 92 mEq/l, respectively), hyperkalaemia (9.6 mEq/l), and metabolic acidosis (pH 7.15, HCO3--10.8 mmol/l, BE -19.5 mmol/l) with normal anion gap were found. Urine analysis showed pH 5, while blood creatinine and urea nitrogen, as well as brain, heart and abdomen ultrasound examinations were normal, without revealing signs of hyperplasia of the adrenal glands and/or abnormalities of the kidneys and the urinary tract. Intravenous (IV) rehydration therapy with sodium chloride and sodium bicarbonate was started, for correction of hyponatremia and metabolic acidosis, respectively. Meanwhile, a treatment with fludrocortisone acetate (0.1 mg/day) and hydrocortisone (maximum dose 10 mg/m2/day) was also begun. Due to persistence of severe hyperkalemia, IV infusion of insulin and rectal, and subsequently oral, sodium polystyrene sulfate administration were performed. Breastfeeding was stopped, and the baby was fed with a special low-potassium formula. Hormonal parameters showed normal renin levels (2.1 ng/dl, normal values [n.v.] 0.25-3.58), significantly increased aldosterone ones (80.6 ng/dl, n.v. 0.37-3.1), aldosterone/renin ratio (38.37, n.v. <20), 17-OH progesterone (>16 ng/ml, n.v. 0.32-3.32), and low of ACTH (2.24 ng/l, n.v. 5-55) and cortisol (7.37 µg/dl, n.v. 6.2-19.4) (Table 1). Furthermore, high urinary levels of sodium (436 mEq/l, n.v. 54-150), and low of potassium (1 mEq/l, n.v. 20-80), in addition to parental consanguinity strengthened the diagnostic suspicion of PHA1. Then, NGS analysis of the genes involved in pseudohypoaldosteronism was performed. The SCNN1A gene mutation c.685-1G>A was identified in the homozygous proband, and in the heterozygous parents. Later, SCNN1A gene sequencing was performed also in the healthy maternal aunt, revealing the same heterozygous mutation.
The following clinical course of the newborn was characterized by miliaria rubra observed in the face (Figure 1), without conjunctivitis and/or other signs of ocular involvement. At the age of two months, because of hypercalciuria, hyperoxaluria and crystals in the left kidney and bladder
(Figure 2), sodium citrate was associated in the treatment. Furthermore, the sweat test detected increased sodium levels (117 mEq/l, n.v. 15-65). He was discharged at 3 months of age in good general condition, adequate weight and length growth, neuromotor development and control of serum electrolytes and hormone levels (Table 1), due to treatment with fludrocortisone acetate (0.1 mg/day), sodium chloride (14 mEq/kg/day divided in 6 administrations), sodium citrate (250 mg/day in 2 divided doses) and sodium polystyrene sulfate (330 mg/kg/day in 2 divided doses), and temporary suspension of vitamin D supplementation.
The child currently is 6 months old, and shows adequate growth: weight 8.1 Kg (58th centile), length 72 cm (98th centile), and head circumference 42.5 cm (25th centile) (according to World Health Organization growth standards for neonatal and infant close monitoring) [7]. He is included in a multidisciplinary follow-up, and still treated with low-potassium formula, as well as oral fludrocortisone acetate (0.1 mg/day), sodium chloride (4.5 mEq/kg/day), sodium citrate (500 mg/day), and sodium polystyrene sulfate (300 mg/kg/day), with satisfying control of hormone levels and serum and urinary electrolytes including calcium, which enabled reintroduction of Vitamin D supplementation (Table 1).
Table 1
serum and urinary electrolytes, and hormonal parameters of our first patient.
|
Admission to NICU (8 days)
|
Discharge (3 months)
|
Follow-up
(6 months)
|
Na (mEq/l)
|
117
|
139
|
139
|
K (mEq/l)
|
9.6
|
4
|
3.91
|
Cl (mEq/l)
|
92
|
106
|
108.3
|
Urinary Na (mEq/l) (n.v. 54-150)
|
436
|
|
352
|
Urinary K (mEq/l) (n.v. 20-80)
|
1
|
|
3
|
ACTH (ng/l) (n.v. 5-55)
|
2.24
|
39.5
|
20
|
Aldosterone (ng/dl) (n.v. 0.37-3.1)
|
80.6
|
6.6
|
<3.7
|
Renin (ng/dl) (n.v. 0.25-3.58)
|
2.1
|
|
<1.8
|
Cortisol (µg/dl) (n.v. 6.2-19.4)
|
7.37
|
|
6.27
|
17-OH progesterone (ng/ml) (n.v. 0.32-3.32)
|
>16
|
3.16
|
1.26
|
Within a detailed medical history of the family, a possible related twenty-year-old girl belonging to the same Sicilian small town, with referred neonatal salt loss syndrome and hyperkalemia, failure to thrive in the first year of life and subsequent normal growth and neurodevelopment, was found. This second patient had a PHA1 clinical diagnosis when she was about one year old. Referring to a remote and unfocused coefficient of consanguinity, the genetic investigation was, then, extended to this further proband and to her family, allowing the identification of the same mutation in the homozygous girl and in the heterozygous parents. She currently is under treatment with low-potassium diet, sodium chloride and ion exchange resin, and has a normal life.