Clinical case 3 3

/ 03

01

Two females – twins

Born at full term, small for gestational
age (2.2 and 1.8 kg)

Twins with non-consanguineous parents

No family history of rickets or metabolic
bone diseases

No history of prolonged neonatal jaundice
that required evaluation

Here we will describe just one of the two
siblings as presentation of the disease was
similar in both sisters.

At 6 months

Physical examination:

Laboratory investigations:

Admitted to hospital with respiratory syncytial
virus bronchiolitis and hypocalcaemia

Open anterior fontanelle
Widening of wrists
Prominent costochondral junctions
Body weight of 4 kg (less than
the 5th percentile)

Next

Persistent rickets, no gain of weight or length
Mild hypotonia and delayed motor development
No reports of acholic stools, jaundice, dark-
coloured urine, or pruritus
No hepatomegaly
Intermittently elevated transaminases
(less than twice the upper limit of normal)
Persistent vitamin D-deficiency: oral Vitamin D
doses were increased

Skeletal survey (X-ray): rachitic changes

Treated with oral calcium and ergocalciferol with
no clinical improvement:

Severe failure to thrive, refractory vitamin D-deficiency
rickets unresponsive to massive doses of vitamin D
and calcium, and mildly elevated liver enzymes

Suspicion of hepatobiliary disorder:

Abdominal ultrasound: mild hepatomegaly
with the absence of focal hepatic lesions or
intrahepatic biliary dilation

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02

Next

Laboratory evaluation:

Subsequent evaluations:

Serum prealbumin, albumin, ammonia,
gamma glutamyl transferase (GGT) levels: normal
Analysis of celiac, hepatitis B and C panels,
MM α-1-phenotype: normal
Lipid profile and faecal elastase: normal

Scleral icterus and hepatomegaly
Feeding intolerance and acholic stools
Delayed motor development, not yet
started walking

At 15 months:

Plasma analysis by gas chromatography/MS:

Very low concentrations of cholic and chenodeoxycholic acid
High concentrations of 3ß,7α-dihydroxy-5-cholenoic and
3ß,7α,12α-trihydroxy-5-cholenoic acids

Serum bile acids analysis by liquid chromatography: normal

Urine bile acids analysis by mass spectrometry: abnormal
urine bile acid profile with the characteristic atypical bile acids
that are the biomarkers for a 3ß-hydroxy-∆5-C27-steroid
oxidoreductase deficiency

Neonatal and adult cholestasis sequencing panel: identified
a mutation in HSD3B7 gene.

Diagnosis of 3β-HSD deficiency

Rickets with evident changes
in skeletal survey

Mild hypotonia

Delayed motor development

Unresponsive to massive
doses of vitamin D and calcium

On follow-up:

Non-consanguineous
healthy parents
Two twins with
same symptoms

No histological investigation

Hypocalcaemia
Hypophosphataemia
Elevated parathyroid hormone
Undetectable 25-OH-vitamin D
Mildly elevated liver enzymes
Normal serum prealbumin,
albumin, ammonia, gamma
glutamyl transferase (GGT) levels

Slow increase of serum bilirubin
Low serum concentrations of
fat-soluble vitamins

Elevated prothrombin time
Elevated partial thromboplastin time
Elevated INR

In this case bile acid synthesis disorder was diagnosed in twins who presented with refractory vitamin D-deficiency, rickets and failure to
thrive, even in the absence of substantial abnormalities in liver function tests.

Hepatomegaly

Icterus

Failure to thrive

03

Previous

01 / 03

Two females – twins

Born at full term, small for gestational
age (2.2 and 1.8 kg)

Twins with non-consanguineous parents

No family history of rickets or metabolic
bone diseases

No history of prolonged neonatal jaundice
that required evaluation

Here we will describe just one of the two
siblings as presentation of the disease was
similar in both sisters.

At 6 months

Physical examination:

Laboratory investigations:

Admitted to hospital with respiratory syncytial
virus bronchiolitis and hypocalcaemia

Open anterior fontanelle
Widening of wrists
Prominent costochondral junctions
Body weight of 4 kg (less than
the 5th percentile)

Next

Persistent rickets, no gain of weight or length
Mild hypotonia and delayed motor development
No reports of acholic stools, jaundice, dark-
coloured urine, or pruritus
No hepatomegaly
Intermittently elevated transaminases
(less than twice the upper limit of normal)
Persistent vitamin D-deficiency: oral Vitamin D
doses were increased

Skeletal survey (X-ray): rachitic changes

Treated with oral calcium and ergocalciferol with
no clinical improvement:

Severe failure to thrive, refractory vitamin D-deficiency
rickets unresponsive to massive doses of vitamin D
and calcium, and mildly elevated liver enzymes

Suspicion of hepatobiliary disorder:

Abdominal ultrasound: mild hepatomegaly
with the absence of focal hepatic lesions or
intrahepatic biliary dilation

Previous

02 / 03

Next

Laboratory evaluation:

Subsequent evaluations:

Serum prealbumin, albumin, ammonia,
gamma glutamyl transferase (GGT) levels: normal
Analysis of celiac, hepatitis B and C panels,
MM α-1-phenotype: normal
Lipid profile and faecal elastase: normal

Scleral icterus and hepatomegaly
Feeding intolerance and acholic stools
Delayed motor development, not yet
started walking

At 15 months:

Plasma analysis by gas chromatography/MS:

Very low concentrations of cholic and
chenodeoxycholic acid
High concentrations of 3ß,7α-dihydroxy-5-cholenoic
and 3ß,7α,12α-trihydroxy-5-cholenoic acids

Serum bile acids analysis by liquid chromatography:
normal

Urine bile acids analysis by mass spectrometry:
abnormal urine bile acid profile with the characteristic
atypical bile acids that are the biomarkers for a
3ß-hydroxy-∆5-C27-steroid oxidoreductase deficiency

Neonatal and adult cholestasis sequencing panel:
identified a mutation in HSD3B7 gene.

Diagnosis of 3β-HSD deficiency

Rickets with evident changes
in skeletal survey

Mild hypotonia

Delayed motor development

Unresponsive to massive
doses of vitamin D and calcium

On follow-up:

Non-consanguineous
healthy parents
Two twins with
same symptoms

No histological investigation

Hypocalcaemia
Hypophosphataemia
Elevated parathyroid hormone
Undetectable 25-OH-vitamin D
Mildly elevated liver enzymes
Normal serum prealbumin,
albumin, ammonia, gamma
glutamyl transferase (GGT) levels

Slow increase of serum bilirubin
Low serum concentrations of
fat-soluble vitamins

Elevated prothrombin time
Elevated partial thromboplastin time
Elevated INR

In this case bile acid synthesis disorder was diagnosed in twins
who presented with refractory vitamin D-deficiency, rickets and
failure to thrive, even in the absence of substantial abnormalities
in liver function tests.

Hepatomegaly

Icterus

Failure to thrive

03 / 03

Previous

CLINICAL
SIGNS

LABORATORY
SIGNS

FAMILY
HISTORY

HISTOLOGICAL
SIGNS

3. Ahmad O, Nogueira J, Heubi JE, Setchell KDR, Ashraf AP. Bile Acid Synthesis Disorder Masquerading as Intractable Vitamin D-Deficiency Rickets. J Endocr Soc. 2018;3(2):397-402.