Journal of Postgraduate Medicine
 Open access journal indexed with Index Medicus & ISI's SCI  
Users online: 7070  
Home | Subscribe | Feedback | Login 
About Latest Articles Back-Issues Articlesmenu-bullet Search Instructions Online Submission Subscribe Etcetera Contact
 ::  Similar in PUBMED
 ::  Search Pubmed for
 ::  Search in Google Scholar for
 ::Related articles
 ::  Article in PDF (1,334 KB)
 ::  Citation Manager
 ::  Access Statistics
 ::  Reader Comments
 ::  Email Alert *
 ::  Add to My List *
* Registration required (free) 

  IN THIS Article
 ::  Abstract
  ::  Introduction
  ::  Case Series
  ::  Discussion
 ::  References
 ::  Article Figures
 ::  Article Tables

 Article Access Statistics
    PDF Downloaded25    
    Comments [Add]    

Recommend this journal


  Table of Contents     
Year : 2023  |  Volume : 69  |  Issue : 3  |  Page : 164-171

Porphyrias: Uncommon disorders masquerading as common childhood diseases

1 Genetic Clinic, Department of Pediatrics, Mumbai, Maharashtra, India
2 Department of Dermatology, Seth G.S. Medical College and K.E.M. Hospital, Parel, Mumbai, Maharashtra, India

Date of Submission31-Aug-2022
Date of Decision17-Jan-2023
Date of Acceptance18-Jan-2023
Date of Web Publication20-Apr-2023

Correspondence Address:
Dr. M Muranjan
Genetic Clinic, Department of Pediatrics, Mumbai, Maharashtra
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jpgm.jpgm_698_22

Rights and Permissions

 :: Abstract 

Porphyrias are a rare group of inborn errors of metabolism due to defects in the heme biosynthetic pathway. The biochemical hallmark is the overproduction of porphyrin precursors and porphyrin species. Afflicted patients present with a myriad of symptoms causing a diagnostic odyssey. Symptoms often overlap with those of common diseases and may be overlooked unless there is heightened clinical suspicion. We are reporting clinical features and diagnostic challenges in four pediatric patients having variegate porphyria, congenital erythropoietic porphyria, acute intermittent porphyria, and erythropoietic protoporphyria (EPP), who presented with diverse multisystem manifestations. This case series illustrates a logical analysis of symptoms and judicious selection of investigations and the role of genotyping in successfully diagnosing porphyrias.

Keywords: Chronic liver disease, hypertension, hyponatremia, inborn errors of metabolism, photosensitivity, seizures

How to cite this article:
Chakraborty A, Muranjan M, Karande S, Kharkar V. Porphyrias: Uncommon disorders masquerading as common childhood diseases. J Postgrad Med 2023;69:164-71

How to cite this URL:
Chakraborty A, Muranjan M, Karande S, Kharkar V. Porphyrias: Uncommon disorders masquerading as common childhood diseases. J Postgrad Med [serial online] 2023 [cited 2023 Sep 24];69:164-71. Available from:

 :: Introduction Top

Porphyrias are a group of related genetic disorders resulting from variants in nine genes coding for eight enzymes of heme biosynthesis.[1],[2] Deficient activity of any one of these enzymes causes a build-up of type-specific porphyrin species in body fluids and tissues [Table 1]. Porphyrias are classified either as hepatic or erythropoietic depending on the site of overproduction of heme precursors, or acute or cutaneous depending on manifestations.[2] Porphyrias are perceived to manifest after puberty, most frequently in early to mid-adulthood.[2] They are considered rare in children due to several factors including lack of easy access to diagnostic tests.[3] Nevertheless, timely recognition and correct diagnosis are critical as an acute crisis of porphyria could be life-threatening and untreated disease could result in permanent neurological morbidity, irreversible liver disease, photomutilation, and development of hepatocellular carcinoma.[2] Additionally, several subtypes of porphyrias now have disease-specific treatments.[4]
Table 1: Classification of porphyrias

Click here to view

The present case series highlights the puzzling nature of the disease with manifestations mimicking other common childhood disease, resulting in mistaken diagnoses in three cases before referral to our institute. This case series aims to raise awareness for suspecting this rare group of diseases and offers a logical pathway to diagnosis.

 :: Case Series Top

Case 1

A 10-year-old girl, symptomatic for one week, was referred with a differential diagnosis of acute gastroenteritis or subacute intestinal obstruction. The illness progressed over the next 3 days in the form of three episodes of generalized tonic-clonic seizures along with behavioral disturbances [Table 2]. The emergence of autonomic disturbances (tachycardia, hypertension, and constipation within the next 48 h) and the presence of hyponatremia led to suspicion of porphyria. Hoesch's test was positive [Figure 1]. Blood and urine porphyrin isomer analysis suggested the probability of acute porphyria [Table 3]. The patient was treated with intravenous tramadol (2 mg/kg) for acute pain for 4 days, and intravenous levetiracetam (20 mg/kg/day twice daily) for seizure control followed by its oral administration. Oral propranolol (1 mg/kg/day 12 hourly) was given for one week for autonomic disturbances. Intravenous 10% dextrose (300 g/day) was administered for the initial two days, followed by an oral carbohydrate-rich diet. The drug of choice, intravenous heme arginate, could not be procured due to financial constraints. The patient improved symptomatically within 48 h. Levels of urinary ALA (aminolevulinic acid) and PBG (porphobilinogen) normalized within 10 days of hospital stay [Table 4]. Porphyrin precursor and porphyrin isomer levels on follow-up are shown in [Table 4]. Diagnosis of variegate porphyria (VP) was confirmed by the detection of a novel variant in the PPOX gene [Table 3].
Figure 1: Urine sample showing pink color (positive result) on Hoesch test

Click here to view
Table 2: Clinical features of the four patients in the present case series

Click here to view
Table 3: Investigations of the four patients in the present case series

Click here to view
Table 4: Follow-up investigations in patient 1

Click here to view

Case 2

An 18 months old developmentally normal boy was referred with complaints of dark red urine [Figure 2]a and staining of diapers soon after birth. Over the next 6 months, he had developed cutaneous lesions over his fingers and cheeks, nail changes [Figure 2]b and [Figure 2]c, and dark discoloration of teeth [Figure 2]d and [Table 2]. Even though Hoesch's test was negative, symptoms were highly suggestive of porphyria. Additional investigations performed [Table 3] were consistent with the diagnosis of congenital erythropoietic porphyria (CEP). Erythrodontia and fluorescence of the urine were demonstrated by Wood's lamp (UV-A light) examination [Figure 2]e and [Figure 2]f. Next-generation sequencing-based testing confirmed the diagnosis of CEP by detection of a known pathogenic variant in the UROS gene[5] [Table 3]. Two packed red cell transfusions (15 cc/kg) were required for treating anemia. Barrier sunscreen, oral beta-carotene (120 mg/per day), vitamin A (1500 IU/day), vitamin D (600 IU/day), and vitamin E (6.5 IU/day) supplements were started. Skin lesions improved gradually after 6 months of treatment [Figure 2]g. The child is currently receiving monthly packed cell transfusions and iron chelation therapy with oral deferasirox at 30 mg/kg once daily. Alloimmune matched donor hematopoietic stem cell transplant has been advised as a curative treatment.
Figure 2: Clinical photographs of patient 2 with congenital erythropoietic porphyria showing a) dark red urine on exposure to light, b) swelling of fingers and irregular whitish nails showing leukonychia with scaling and pigmented striae, blisters and hyperpigmentation of skin exposed to sunlight, c) multiple small hyperpigmented lesions on cheeks, upper lip and erosions with dry crusting over nose, d) reddish discoloration of teeth, e) Wood's lamp examination showing erythrodontia - red fluorescence of the teeth and f) Wood's lamp examination showing red fluorescence of patient's urine sample (arrow) and control, g) resolving skin lesions after treatment

Click here to view

Case 3

An 8-year-old boy was referred to our institute as a case of febrile encephalopathy with a fifth episode of seizure and altered sensorium. There was a history of intermittent frontal throbbing headaches with retrobulbar pain, abdominal pain, and behavioral disturbances for a month [Table 2]. The father who had similar complaints of headaches with emotional lability and one episode of seizure in childhood had not been evaluated and symptoms did not recur. There was no history of similar symptoms in any other family members. The child's illness progressed to status epilepticus during his ward stay. Seizures worsened despite treatment with intravenous phenytoin (5 mg/kg/day, twice daily) and sodium valproate (30 mg/kg/day, twice daily). They eventually subsided with midazolam infusion (6 μg/kg/min). Examination findings are described in [Table 2]. Magnetic resonance imaging (MRI) brain showed symmetric parieto-occipital white matter edema and hyperintense signals on T2 and fluid-attenuated inversion recovery (FLAIR) sequences suggestive of posterior reversible encephalopathy syndrome (PRES) [Table 2]. Porphyria was subsequently suspected and Hoesch's test was positive. Diagnostic investigations for porphyria are presented in [Table 3]. Our presumptive diagnosis was acute intermittent porphyria (AIP) based on PBG deaminase activity being <50% of normal. The family could not afford genetic testing. Hypertension was controlled with oral prazosin (0.2 mg/kg/day, twice daily). Phenytoin and sodium valproate were discontinued as they are porphyrinogenic.[6] Instead, oral levetiracetam (20 mg/kg/day, twice daily) was introduced. Oral tramadol (2 mg/kg/dose) alternating with fentanyl patches was administered for the pain while autonomic disturbances were controlled with oral propranolol (1 mg/kg/day, twice daily). The child gradually improved over 72 h, oral prazosin was discontinued with no further hypertension or seizures. Subsequently, the child's abdominal pain and headache also subsided.

Case 4

A 10-year-old boy was brought with complaints of photosensitive skin lesions on sun-exposed areas since 4 years and abnormal nails since 7 years of age. He also had a past history of episodes of abdominal pain, vomiting, and jaundice at 5 years of age [Table 2]. He was referred with a probable diagnosis of systemic lupus erythematosus or autoimmune hepatitis. On examination, there was no icterus. There were macules over the face with waxy thickening of the skin, crusted erosions over the nose, thick nails with leukonychia, and whitish striae and xerosis involving the hands and feet [Figure 3]a, [Figure 3]b, [Figure 3]c and [Table 2]. Investigations are described in [Table 3]. Ultrasonography of the abdomen was suggestive of liver cirrhosis with splenomegaly. The hepatoportal Doppler study ruled out portal hypertension. Liver biopsy showed expansion of portal tracts with lymphocytic and plasma cell infiltration, ductular proliferation and fibrosis, and the presence of granular reddish-brown material in the Kupffer cells and bile canaliculi [Figure 3d]. Polarizing microscopy of the pigment revealed crystals with Maltese cross configuration with birefringence limited to the periphery of the deposits [Figure 3]e and [Figure 3]f. Orcein staining was focally positive and hepatic copper content was elevated. These histological features were indicative of hepatic cirrhosis due to porphyria.
Figure 3: Clinical photograph of patient 4 with erythropoietic protoporphyria showing a) multiple, small hyperpigmented lesions on cheeks, upper lip, and erosions with crusting over the nose, b) hyperpigmentation and xerosis of hands with leukonychia and white striae, c) cutaneous hyperpigmentation, xerosis, and sclerosis of feet with thick nails, d) liver histopathology (H & E stain, 400X) showing reddish brown pigment in bile canaliculi and Kupffer cells, e) polarizing microscopy (400X) of pigment in Kupffer cells showing birefringent crystals, f) Maltese cross configuration of crystals (1000X) and g) follow-up after four months of treatment showing resolving skin lesions

Click here to view

Hoesch's test was negative. Diagnosis of autosomal recessive erythropoietic protoporphyria (EPP) was confirmed based on blood porphyrin isomer pattern and a novel variant in the FECH gene [Table 3]. Treatment included titanium-based barrier sunscreens and clothing to avoid sun exposure. Oral beta-carotene (40 mg thrice daily), vitamin D (600 IU/day), and vitamin E (7.5 IU/day) supplementation were given along with ursodeoxycholic acid (300 mg twice daily). On follow-up, the skin lesions gradually resolved almost completely over a period of 4 months [Figure 3]g.

Genetic counseling was provided for the four families, stressing the need for screening family members and first-degree relatives (patients 1 and 3 with autosomal dominant acute porphyria) and avoidance of porphyrinogenic drugs and other precipitating factors. A parental segregation study was advised for all patients. Since the father of patient 3 had symptoms of porphyria, a recurrence risk of 50% in future offspring was conveyed. For patients 2 and 4, the recurrence risk of 25% in future offspring was conveyed.

 :: Discussion Top

Four patients with different types of porphyrias reported in the present case series illustrate the diagnostic challenges in childhood. Patients 1 and 3 presented with common gastrointestinal symptoms and seizures, patients 2 and 4 had cutaneous symptoms of phototoxicity, while evidence of transfusion-dependent anemia and chronic liver disease was observed in patients 2 and 4, respectively. Red urine and discolored teeth were the other two striking symptoms observed in patient 2.

In Europe, porphyria cutanea tarda (PCT) is the commonest subtype and, CEP is the rarest. EPP is the commonest type in childhood, whereas hepatic porphyrias manifest in adolescents or adults.[2] Only 2.2% of 269 patients with AIP in two large series of patients from Europe were younger than 15 years of age.[7] Thus, the perception of porphyrias as an adult disease could result in suboptimal awareness among general practitioners and pediatricians,[3] and consequently hamper early suspicion and diagnosis.

Other factors also contribute to difficulties in the recognition of symptoms of porphyria in children: the diseases are often latent or subclinical.[3] Due to low penetrance in autosomal dominant porphyrias [AIP, hepatic coproporphyria (HCP), EPP, VP, and familial PCT], a history of symptomatic family members may be lacking.[2] Even when there is a family history with the father having symptoms in childhood, as seen in patient 3, poor awareness of these rare disorders results in a lack of diagnosis. Symptoms of acute hepatic porphyrias are triggered by environmental factors such as exposure to progesterone, steroids, progestin-containing oral contraceptives, antiepileptics, antihypertensives, antimicrobials, drugs that induce the hepatic ALAS1 (δ-aminolevulinate synthase-2), and cytochrome P450 enzymes, nutritional factors like reduced intake of calories and carbohydrates, or metabolic stress in illnesses, weight loss, or major surgeries.[7] In these subtypes, lack of exposure to precipitating factors such as drugs, hormones, and fasting in children, and alcohol consumption in adolescents would prevent the development of manifestations.[3]

Alternatively, a wide variability of manifestations could be a barrier to suspecting porphyria. Acute porphyrias can cause neurovisceral symptoms like autonomic disturbances, paresis/muscle weakness, respiratory failure, hypoactive/absent tendon reflexes, cranial/peripheral neuropathy, seizures, and encephalopathy and are associated with elevated levels of porphyrin precursors PBG and/or ALA.[8] Photosensitivity is a symptom of cutaneous (non-acute) porphyrias and CEP presents with chronic hemolytic anemia.[9] Unusual symptoms like the pink or red color of urine [AIP, CEP, and hepatoerythropoietic porphyria (HEP)], staining of the diaper, and reddish-brown discoloration of teeth [CEP and HEP] indicative of these rare diseases facilitate diagnosis as experienced with patient 2.[2] However, pink urine is reported in just 25% of cases having AIP.[6] Yet, when porphyrias manifest with non-specific symptoms like nausea, vomiting, abdominal pain, abdominal distension, constipation, seizures, or behavioral abnormalities,[9] they resemble signs and symptoms of common childhood illnesses like acute gastroenteritis, acute appendicitis, intestinal obstruction, acute pancreatitis, psychosis, or encephalitis or encephalopathy[6] as noted in patients 1 and 3. Diagnostic delays in these cases are inadvertent. Nevertheless, red flags that should arouse suspicion of porphyrias in such cases are autonomic disturbances (tachycardia, hypertension, sweating, and tremors) and hyponatremia, which were clues leading to suspicion of porphyria in patients 1 and 3.[7] Symptoms of swelling and pain in extremities (CEP and EPP) sometimes mimic rheumatic or autoimmune disorders[8],[10] and positive antinuclear antibodies (ANA) serology as seen in patient 4 could then cause diagnostic confusion. Lala et al.[10] also reported a 5-year-old female manifesting with burning, itching, and swelling of hands and feet who had a positive ANA test and was subsequently diagnosed to have EPP.

[Figure 4] represents a simple algorithm for the diagnosis of porphyrias. First-line investigations for porphyria are a quantitative estimation of urinary PBG and ALA levels during acute episodes followed by a panel of tests that measure porphyrins and the ratio of their isomers in blood and urine, blood porphyrin fluorescence emission spectrum, erythrocyte-free and zinc protoporphyrin, and erythrocyte porphobilinogen deaminase activity.[1],[11] Hoesch's test which detects urinary PBG, is a bedside screening test performed by adding two drops of urine to 1 ml of Ehrlich reagent.[1] A positive result is the instantaneous development of cherry red/pink color on top of the solution.[1] This test is positive in AIP, VP, and HCP. Hoesch's test is negative in PCT and erythropoietic porphyrias where urinary PBG is not elevated as seen in patients 2 and 4.[9],[11] Nevertheless, diagnostic investigations must be pursued despite negative Hoesch's test when manifestations are highly suspicious for porphyria.
Figure 4: Algorithm for the diagnosis of porphyrias. ALA: aminolevulinic acid, PBG: porphobilinogen, AIP: acute intermittent porphyria, HCP: hepatic coproporphyria, VP: variegate porphyria, PCT: porphyria cutanea tarda , CEP: congenital erythropoietic porphyria, ADP: ala dehydratase deficiency porphyria, EPP: erythropoietic protoporphyria, XLPP: x-linked protoporphyria, RBC: red blood cell

Click here to view

Molecular confirmation of the diagnosis is essential as there is an overlap of manifestations between the various subtypes[9] as evident in patient 1 who was clinically suspected to have AIP on basis of symptoms but molecular testing revealed an alternate diagnosis of variegate porphyria. Correct diagnosis is critical for type-specific therapy and for screening of at-risk family members who may have a latent or asymptomatic disease (who may directly benefit from preventing acute episodes by avoiding exposure to precipitating factors).[2],[9] As porphyrias display autosomal dominant (AIP, VP, HCP, PCT), autosomal recessive (aminolevulinic acid dehydratase deficiency porphyria, CEP, EPP), or X-linked inheritance (X-linked porphyria),[2] diagnosis also aids in genetic counseling to accurately predict recurrence risk in family members.

Avoiding porphyrinogenic antiepileptic drugs is an important aspect of management during acute episodes presenting with seizures.[8],[12] Correct suspicion of porphyria would dictate the choice of safe antiepileptic drugs to treat seizures with benzodiazepines, levetiracetam, gabapentin, or vigabatrin.[6] This aspect is illustrated in patient 3 where phenytoin and sodium valproate were inadvertently administered for controlling seizures before porphyria was suspected resulting in the worsening of seizures.

To conclude, though porphyrias are rare in children, unexplained neurovisceral or phototoxic symptoms should arouse suspicion and trigger a panel of investigations. Relying solely on Hoesch's test can be misleading as this screening test can give false negative results in some subtypes. Molecular confirmation is mandatory as there is considerable overlap in clinical and biochemical features between the various subtypes. Molecular diagnosis also facilitates family screening, genetic counseling, and timely treatment.


The authors thank Dr. Pragati Sathe, Associate Professor, Department of Pathology, KEM Hospital, for reporting liver histopathology. The authors are also grateful to Dr. Anil Jalan, Director, Navi Mumbai Institute of Research in Mental and Neurological Handicap, for performing biochemical analysis of all the patients and Centogene AG for performing molecular testing free of charge.

Declaration of patient consents

The authors certify that appropriate patient consents were obtained

Financial support and sponsorship


Conflicts of interest

Dr. Sunil Karande is the Editor of the Journal of Postgraduate Medicine.

 :: References Top

Di Pierro E, De Canio M, Mercadante R, Savino M, Granata F, Tavazzi D, et al. Laboratory diagnosis of porphyria. Diagnostics 2021;11:1343.  Back to cited text no. 1
Ramanujam V-MS, Anderson KE. Porphyria diagnostics – Part 1: A brief overview of the porphyrias. Curr Protoc Hum Genet 2015;86:17.20.1-17.20.26.  Back to cited text no. 2
Badcock NR, O'Reilly DA, Zoanetti GD, Robertson EF, Parker CJ. Childhood porphyrias: Implications and treatment. Clin Chem 1993;39:1334–40.  Back to cited text no. 3
4. Western Springs: American Porphyria Foundation. Available from: [Last accessed on 2022 Aug 29].  Back to cited text no. 4
National Center for Biotechnology Information. ClinVar; [VCV001452604.2], [Last accessed on 2023 Feb 25].  Back to cited text no. 5
Bolia R, Srivastava A, Poddar U, Yachha SK. Acute intermittent porphyrias: A missed diagnosis in pre-pubertal children with recurrent abdominal pain. Tropical Gastroenterol 2015;36:263–6.  Back to cited text no. 6
Balwani M, Descnick RJ. The porphyrias: Advances in diagnosis and treatment. Blood 2012;120:4496–504.  Back to cited text no. 7
Indika NLR, Kesavan T, Dilanthi HW, Jayasena KLSPKM, Chandrasiri NDPD, Jayasinghe IN, et al. Many pitfalls in diagnosis of acute intermittent porphyria: A case report. BMC Res Notes 2018;11:552.  Back to cited text no. 8
Balwani M, Singh P, Seth A, Debnath EM, Naik H, Doheny D, et al. Acute intermittent porphyria in children: A case study and review of the literature. Mol Genet Metab 2016;119:295–9.  Back to cited text no. 9
Lala SM, Naik H, Balwani M. Diagnostic delay in erythropoietic protoporphyria. J Pediatr 2018;202:320–3.  Back to cited text no. 10
Woolf J, Marsden JT, Degg T, Whatley S, Reed P, Brazil N, et al. Best practice guidelines on first-line laboratory testing for porphyria. Ann Clin Biochem 2017;54:188–98.  Back to cited text no. 11
Sánchez-Soler MJ, Barreda- Sánchez M, Ballesta-Matínez MJ, Glóver G, Guillén-Navarri E. Acute intermittent porphyria in a paediatric population in the region of Murua: Phenotype and prevalence. An Pediatr (Barc) 2016;84:114-20.  Back to cited text no. 12


  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

  [Table 1], [Table 2], [Table 3], [Table 4]


Print this article  Email this article
Online since 12th February '04
2004 - Journal of Postgraduate Medicine
Official Publication of the Staff Society of the Seth GS Medical College and KEM Hospital, Mumbai, India
Published by Wolters Kluwer - Medknow