Clinical case 22

/ 03

01

Male

Second child of unrelated healthy
parents

At 27 months:

Physical examination:

Normal urine analysis

Abdominal ultrasound:

Progressively worsening hepatomegaly
over the last year
Failure to gain weight

No jaundice in the neonatal period or
thereafter, no pruritus or steatorrhoea

Hepatomegaly (about 5 cm below the rib),
without splenomegaly or jaundice
Weight below the 3rd percentile

Signs of liver damage
Bile duct malformation or obstruction
Multiple cystic images in both kidneys,
suggestive of nephrocalcinosis

Next

Laboratory analysis:

Tests for conventional pathogens excluded a possible infective
origin:

Low coagulation factor levels and their subsequent
normalisation with oral intake of vitamin K:

Low level of vitamin E (37 μg/dL)
Vitamin D and vitamin A in the normal range

suspicion of malabsorption of other fat-soluble
vitamins

Confirmation of fat-soluble vitamin deficiencies

Celiac serology was negative, as well as liver
autoimmunity workup, alpha-1-antitripsin
blood levels and cystic fibrosis phenotype and
genetic study
Other metabolic diseases were excluded

Epstein Barr, Cytomegalovirus, Herpes simplex 1 and 2,
Toxoplasma gondii, Parvovirus B19, Hepatitis A, B and C,
Human Immunodeficiency Virus

Low levels of factor VII (61.3%) and factor
X (47.5%), which were subsequently normalised
with oral vitamin K supplementation

Slight increase in aspartate aminotransferase
(AST: 53 mU/mL)
Other routine tests were normal (including alanine
aminotransferase, total and direct bilirubin, GGT,
total bile acids, albumin, cholesterol, triglycerides)
A slightly elevated international normalised ratio (1.41)
with a low prothrombin ratio (58%) prompted
investigation of coagulation factors:

Previous

02

Diagnosis of 3β-HSD deficiency

Liver gene panel analysis showed a novel single homozygous
variant in the HSD3B7 gene.
Qualitative and quantitative urinary bile acid analysis
showed high levels of unusual metabolites and the absence
of primary bile acids

Mild liver dysfunction with normal GGT + normal serum
bile acid levels + fat soluble vitamins K and E
malabsorption = suspicion of BASD

At 32 months:

Next

Failure to gain weight

Hepatomegaly

Non-consanguineous
healthy parents

No histological
investigation

Increased AST
Normal GGT activity
Normal serum total bile acids level

Cholestasis is usually the biochemical and histologic hallmark of a 3β-HSD deficiency. In this case, the child presented no clinical or laboratory
evidence of overt cholestasis, neither in the first months of life, nor at diagnosis. The observation illustrates atypical clinical features: the child
was nearly asymptomatic apart from hepatomegaly and failure to gain weight. Moreover, the malabsorption of fat-soluble vitamins was clinically
asymptomatic and could be demonstrated only by targeted laboratory investigations.

Deficiency of vitamin K
and vitamin E

Previous

03

01/ 03

Male

Second child of unrelated healthy
parents

At 27 months:

Physical examination:

Normal urine analysis

Abdominal ultrasound:

Progressively worsening hepatomegaly
over the last year
Failure to gain weight

No jaundice in the neonatal period or
thereafter, no pruritus or steatorrhoea

Hepatomegaly (about 5 cm below the rib),
without splenomegaly or jaundice
Weight below the 3rd percentile

Signs of liver damage
Bile duct malformation or obstruction
Multiple cystic images in both kidneys,
suggestive of nephrocalcinosis

Next

Laboratory analysis:

Tests for conventional pathogens excluded a
possible infective origin:

Low coagulation factor levels and their subsequent
normalisation with oral intake of vitamin K:

Low level of vitamin E (37 μg/dL)
Vitamin D and vitamin A in the normal range

suspicion of malabsorption of other fat-soluble
vitamins

Confirmation of fat-soluble vitamin deficiencies

Celiac serology was negative, as well as liver
autoimmunity workup, alpha-1-antitripsin
blood levels and cystic fibrosis phenotype and
genetic study
Other metabolic diseases were excluded

Epstein Barr, Cytomegalovirus, Herpes simplex 1 and 2,
Toxoplasma gondii, Parvovirus B19, Hepatitis A, B and C,
Human Immunodeficiency Virus

Low levels of factor VII (61.3%) and factor
X (47.5%), which were subsequently normalised
with oral vitamin K supplementation

Slight increase in aspartate aminotransferase
(AST: 53 mU/mL)
Other routine tests were normal (including alanine
aminotransferase, total and direct bilirubin, GGT,
total bile acids, albumin, cholesterol, triglycerides)
A slightly elevated international normalised
ratio (1.41) with a low prothrombin ratio (58%)
prompted investigation of coagulation factors:

Previous

02 / 03

Diagnosis of 3β-HSD deficiency

Liver gene panel analysis showed a novel single
homozygous variant in the HSD3B7 gene.
Qualitative and quantitative urinary bile acid
analysis showed high levels of unusual metabolites
and the absence of primary bile acids

Mild liver dysfunction with normal GGT + normal serum
bile acid levels + fat soluble vitamins K and E
malabsorption = suspicion of BASD

At 32 months:

Next

Failure to gain weight

Hepatomegaly

Non-consanguineous
healthy parents

No histological
investigation

Increased AST
Normal GGT activity
Normal serum total bile acids level

Cholestasis is usually the biochemical and histologic
hallmark of a 3β-HSD deficiency. In this case, the child
presented no clinical or laboratory evidence of overt
cholestasis, neither in the first months of life, nor at
diagnosis. The observation illustrates atypical clinical
features: the child was nearly asymptomatic apart
from hepatomegaly and failure to gain weight. Moreover,
the malabsorption of fat-soluble vitamins was clinically
asymptomatic and could be demonstrated only by targeted
laboratory investigations.

Deficiency of vitamin K
and vitamin E

Previous

03 /03

CLINICAL
SIGNS

LABORATORY
SIGNS

FAMILY
HISTORY

HISTOLOGICAL
SIGNS

2. Bossi G, Giordano G, Rispoli GA, et al. Atypical clinical presentation and successful treatment with oral cholic acid of a child with defective bile acid synthesis due to a novel mutation in the HSD3B7 gene. Pediatr Rep 2017;9(3):7266. doi: 10.4081/pr.2017.7266 [published Online First: 2017/10/31]